reviewing of synthesis and computational studies of ... · derivatives are shown to exhibit...

*Corresponding author: H. S. Mohamed, Email: [email protected] page 183 of 232

Journal of Chemical Reviews, 2019, Volume 1, Issue 3, Pages 183-232

Reviewing of Synthesis and Computational Studies of Pyrazolo

Pyrimidine Derivatives

Receive Date: 11 Jun 2019, Revise Date: 24 June 2019, Accept Date: 24 June 2019

Abstract: In this review we synthesized and conducted a computational studies on Pyrazolo pyrimidine’s

derivatives that were carried out through density functional theory level utilizing HF/6−311+G**and

B3LYP/6−311+G**. Charge transfer occured through molecule was shown by the calculation of HOMO and

LUMO energies. The electric dipole moment values (l) of the molecule were counted calculations of DFT.

Some geometrical and structural parameters such as total energies (E), relative energies (DE), (bond length in

Å, angles in degree), energy gap, relative Gibbs free energy, dipole moment, and molecular electrostatic

potentials (MEP) were studied. DOI: 10.33945/SAMI/JCR.2019.3.3

Keywords: GAUSSIAN09, DFT, HOMO-LUMO, pyrazolo pyrimidine derivatives, quantum chemical

calculation.

Graphical Abstract:

Hussein Shaban Hussein Mohamed a,*, Sayed Abdelkader Ahmed b

a Research Institute of Medicinal and Aromatic Plants (RIMAP), Beni-Suef University, Beni-Suef, Egypt

b Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

Review Article

mailto:[email protected]

http://www.jchemrev.com/

https://crossmark.crossref.org/dialog/?doi=10.33945/SAMI/JCR.2019.3.3

Journal Of Chemical Reviews Review

page 184 of 232

Biography:

Hussein S. H. Mohamed Was born Beni-Suef (Egypt) in 1980, obtained his

Ph.D. degree in Organic chemistry in 2015 under the supervisor of Prof. Dr.

Ahmed Elghandour and Prof. Dr. Sayed A. Ahmed. Later on, he is currently

working as Senior Researcher in Natural Products of Research Institute of

Medicinal and Aromatic Plants (RIMAP), Beni-Suef University. He has been

actively involved Synthesis of Heterocyclic compounds and its applications in

biological activities, recently he interested in Removal of dyes and heavy metals

from wastewater by different synthesized compounds.

Sayed A. Ahmed Has completed his Ph.D under the supervision of Professor

Galal Elgemie and Prof. Dr. Ahmed Elghandour in the Department of

Chemistry at Beni-Suef University, Egypt. He currently works as a full

professor in Organic Chemistry at Beni-Suef University Egypt. His studies

focused on organic synthesis of Organic compounds and he has published more

than 100 papers. He is a Dean of Faculty of Earth Sciences, Beni-Suef

University Egypt. He has received several national and international awards.

1. Introduction

Heterocyclic pyrimidine nucleus includes four carbon

and two nitrogen atoms and is pharmacologically in

active; however, its synthetic derivatives have

important roles in pharmaceutical applications [1-3].

The properties are demonstrated by their hydrogen

and bonding systems. They belong to the family of

nucleic acids. Nucleic acids are of great interest,

since, they have role in the manufacture of proteins

and the functions of the cells in living organisms [4-

6]. For example Pyrazolo[3,4-d]pyrimidine

derivatives are shown to exhibit anti-amoebic activity

[7-13] and are potential anti-inflammatory agents [14,

15], anti-coagulation inhibitors [16], xanthine oxidase

inhibitors [17], antiproliferative and proapoptotic

agents in various tumor types [18,19]. They are called

SRC kinase inhibitors [20] and are beneficial in

human cancers treating sustaining oncogenic

activation of RET [21]. After the knowing of scaled

quantum mechanical (SQM) calculations, the

philosophy of computational methods of vibrational

spectroscopy [22-25] were changed significantly. The

most applied spectroscopic methods by organic

chemists for the characterization of compounds are

ultra-violet, IR, NMR, and mass spectroscopy. IR

measurement through liquid mixtures supplies an

excellent tool to investigate inter and intramolecular

interactions between like and unlike molecules. The

density functional theory has become a great method

for the description of vibrational spectra and

molecular structure. Completed by a visualization

program, the assignments can accurately be made [26-

28]. The advance in the graphic and computational

devices has increased the significance of MEP

surfaces, highest occupied molecular orbital (HOMO)

and lowest unoccupied molecular orbital (LUMO) as

tools for studying molecular reactivities, interactions,

charge transfers and other molecular properties [29-

34]. These characteristics are the highest occupied

molecular orbital energy EHOMO, the lowest

unoccupied molecular orbital energy Elumo, energy gap

ΔE, dipole moment μ, total energy ET, activation

energy Ea, absorption maximum λmax and factor of

oscillation f(SO). The geometry of the systems has

been improved at the B3LYP /6-31G (d) [35-38]

computational level. As per the computations, the

molecules concerned to energy minima on the

Potential Energy Surface (PES). The Gaussian-09

program was used for all this calculations [39-42].The

density functional used this form:

Exc= (1-α0 )EXLSDA +α0EX

HF +αX ∆EXB88+αCEc

LYP + (1-

αC)ECVWN

2. Synthesis and Computational Studies of

Pyrazolo[3,4-d]Pyrimidine

2.1. 4- Aminopyrazolo[3,4-d]pyrimidine

The theoretical UV–Vis spectrum is used to detect this

compound using CIS method and the electronic

properties, such as HOMO and LUMO energies, were

perfected by time-dependent DFT (TD-DFT)

approach. Charge transfer occurs within the molecule

was shown by HOMO and LUMO energies

calculations. The first order hyperpolarizability (β0) of

this molecular system and related properties (β, α0 and

∆α) of 4-APP are computed using DFT/6-31G (d)

method on the finite-field approach. The Mulliken


page 185 of 232

charges, the values of electric dipole moment (µ) of

the molecule were calculated utilizing DFT

calculations. They used natural bond (NBO) analysis

to compute The diversity in electron density (ED) in

the antibonding orbitals and stabilization energies

giving clear evidence of stabilization originating in

the hyper conjugation of hydrogen-bonded

interactions [43].

2.1.1. Structure of 4-aminopyrazolo[3,4-d]pyrimidine

Scheme 1. Structure of 4-aminopyrazolo[3,4-d]pyrimidine

2.1.2. Computational

Gaussian 09W software package used to calculate the

energy and dipole moment of tautomer [44], using the

B3LYP functional [45,46] combined with standard 6-

31G* basis set.

In the Table 1 Prabavathi, et al. reported that the total

energies, dipole moment and their relative energies of

various tautomer of 4-APP were computed at

B3LYP/6-31G* level.

We can realize from Table 1 that for 4-APP the

energies of the tautomers are in the following order

(1a) < (1b) < (1c) < (1d) < (1e) < (1f) < (1g) < (1h) <

(1i) < (1j) < (1k) < (1L) < (1m) < (1n) < (1o) < (1p).

It was found that the amino-N(1)H tautomer has the

lowest energy and is the most stable form.

Xue et al. utilizing the computed geometrical

parameters for 4-APP (as it contains both a pyrimidine

ring and an imidazole ring) which are parallel with

some of the purine derivatives [47,48] (6-aminopurine

and adenine) for the possible bond lengths and bond

angles. So it was predicted that the bond length and

bond angle agree with adenine parameters obtained in

Table 3.

fgjhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhkkkkkkkkkkkkkkk

Figure 1. Tautomers of 4-aminopyrazolo[3,4-d]pyrimidine.


page 186 of 232

Through Table 4 the values of the polarizabilities (α)

and hyperpolarizability (β) of the Gaussian 09 output,

Data et al. found that the extent of ᴨ electron

delocalization control the ground-state dipole moment

and the hyperpolarizability, which relies on the

structural details of the molecules [49].

The six peaks of 4-APP appeared at 1587, 1580,

1478, 725 cm-1 in both IR and Raman spectra and the

IR bands at 1606, and 1512 cm-1 are attributed to ring

C–N stretching vibrations. Analogical bands are

theoretically calculated at 1633, 1612, 1563, 1512,

1466, 705 cm-1 with a PED contribution in the range

58–35% at 6-31G** level.

Table 1. Energy and dipole moment of 4-aminoPyrazolo[3,4-d]pyrimidine.

Tautomera Total energy

(Hartree) B3LYP/

631_G*

Dipole moment

(Debye) B3LYP/

631_G*

Relative

energies

(kJ mol-1)

4-Aminopyrazolo [3 4-d]pyrimidine

1a -467.238374 1.7170 0.0

1b -467.218458 5.5250 52.3

1c -467.215798 6.2607 59.3

1d -467.198521 11.2556 104.6

1e -467.197957 4.8652 106.1

1f -467.185872 1.9407 137.8

1g -467.185169 4.5492 139.7

1h -467.184202 7.9895 142.2

1i -467.180848 3.8361 151.0

1j -467.166858 1.1979 187.8

1k -467.157364 8.5522 212.4

1l -467.154937 10.8967 219.1

1m -467.154623 8.6543 219.9

1n -467.154076 6.1545 221.3

1o -467.138857 9.2026 261.3

1p -467.126886 10.6410 292.7

a For the tautomeric figures.

Table 2. Theoretical computed energies (a.u.), energies (Kcal Mol-1), Rotational constant (GHZ), entropy (Cal mol-1 k-1) and Dipole moment (Debye).

Structural parameter B3LYP/6-31G*

4-APP

B3LYP/6-31G**

4-APP

Total energy(thermal) Etotal 75.22 75.17

Heat capacity at const. Volume ,Cv 27.84 27.86

Entropy ,S 83.15 83.11

Vibrational energy Evib 73.45 73.40

Zero-point vibrational Energy , E0 70.82 70.78

Rotational constant

A

B

C

2.403

1.493

0.922

2.404

1.493

0.922

Dipole moment

µx

µy

µz

µtotal

-0.4060

-1.4263

1.3911

2.0332

0.3975

-1.5064

1.3441

2.0578


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Table 3. Optimized geometrical parameters of 4-aminoPyrazolo[3,4-d]pyrimidine obtained by B3LYP/6-31G* and B3LYP/6-31G** density functional calculations.

Bond length Value (Å) Bond angle Value (o)

6-31G* 6-31G** 6-31G* 6-31G**

N1–N2 1.36 1.36 N1–N2–C3 105.81 105.85

C3–N2 1.32 1.32 N2–C3–C4 111.19 111.12

C4–C3 1.42 1.42 C3–C4–C5 140.36 140.33

C5–C4 1.41 1.41 C4–C5–N6 119.81 119.78

N6–C5 1.33 1.33 C5–N6–C7 118.25 118.29

C7–N6 1.34 1.34 N6–C7–N8 128.61 128.57

N8–C7 1.32 1.32 C7–N8–C9 111.80 111.82

C9–N8 1.34 1.34 C9–N1–H10 127.62 127.49

H10–N1 1.00 1.00 N2–C3–H11 119.38 119.46

H11–C3 1.08 1.08 C4–C5–N12 122.43 122.44

N12–C5 1.38 1.38 C5–N12–H13 111.79 111.76

H13–N12 1.01 1.01 C5–N12–H14 108.53 108.48

H14–N12 1.01 1.01 N6–C7–H15 115.20 115.22

H15–C7 1.08 1.08 C4–C3–N2–N1 0.0 0.0

C5–C4–C3–N2 180.0 180.0

N6–C5–C4–C3 -180.0 -180.0

C7–N6–C5–C4 0.0 0.0

N8–C7–N6–C5 0.0 0.0

C9–N8–C7–N6 0.0 0.0

H10–N1–C9–N8 0.0 0.0

H11–C3–N2–N1 180.0 180.0

N12–C5–C4–C3 6.0 6.0

H13–N12–C5–C4 -46.0 -46.0

H14–N12–C5–C4 -161.0 -161.0

H15–C7–N6–C5 180.0 180.0

a For the tautomeric figures.

Table 4. Vibrational spectral data (cm-1)

No Observed Calculated frequency (cm-1) with B3LYP/6-31G** force field TED (%) among

type of internal

coordinatesc

Infrared Raman Unscaled Scaled IRa(Ai) Ramanb(Ii)

1 3318 _ 3644 3318 14.89 1.07 NــH Stretching

2 3135 _ 3553 3135 94.00 3.83 NH2ass(95)

3 _ 3102 3504 3102 22.60 72.71 NH2ss(95)

4 3060 _ 3337 3079 4.02 10.57 CــH(99)

5 3030 _ 3261 3010 29.03 1.14 CــH(99)

6 1677 1675 1670 1668 220.69 17.93 NH2sci(54)

7 1606 _ 1630 1633 190.18 29.66 CــN(51), NH2Sci(26)

8 1587 1585 1611 1612 64.95 4.24 CــN(43), bCCH(32)


page 188 of 232

9 1580 1580 1511 1563 4.36 25.17 CــN(54), bCCH(29)

10 1512 _ 1488 1512 165.42 19.41 CــN(58), CــC(16)

11 1478 1478 1450 1466 84.69 26.12 CــN(49), bCCH(22)

12 1398 _ 1389 1407 4.18 4.10 bCCH(52), CــN(16)

13 _ 1394 1368 1387 9.63 23.17 CــN(57), CــC(19)

14 1340 1337 1336 1335 8.02 10.30 CــC(42), CــN(35)

15 1339 _ 1332 1325 180.20 3.14 bNNH(47), CــN(16)

16 1265 _ 1283 1265 45.52 3.62 bCCH (59), bNNH

(15)

17 1199 _ 1211 1200 40.66 9.27 CــC(41), CــN(22)

18 _ 1154 1160 1147 11.30 12.00 bring2(35), CــN(27)

19 1067 1066 1075 1069 34.15 8.14 NــN(78), bNNH(9)

20 1029 1031 1053 1035 22.96 8.31 NH2roc(54), CــN(37)

21 962 939 981 972 150.30 1.43 CــC(53), bring2(18)

22 903 898 947 914 100.47 2.83 bring1(54), CــC(17)

23 900 900 906 895 11.79 2.12 gCH(59), bring2 (17)

24 870 _ 871 856 70.71 1.02 gHN(77), tring2(15)

25 796 796 853 805 15.64 1.94 gCH(31), tring1(27)

26 785 _ 800 775 115.94 1.51 gCH(30), tring1(29)

27 725 725 713 705 2.87 18.67 CــN(30), CــC(24)

28 693 _ 681 701 17.42 0.08 tring2(82), tButt(7)

29 636 _ 659 633 30.89 1.29 gCN(39), tring1(30)

30 609 615 608 594 0.23 8.34 bring2(31), CــC (29)

31 549 _ 573 554 57.46 2.13 tring1(46), gNH(23)

32 527 527 525 526 0.56 4.51 bring1(74), CــN(12)

33 _ _ 511 508 3.66 2.77 bring1(32), bCN(31)

34 _ _ 499 488 34.03 2.12 gNH(58), tring2(30)

35 _ _ 353 337 69.94 1.98 tNH2(68), gHN(19)

36 _ _ 299 292 3.05 0.06 tring1(35), tring2(25)

37 _ _ 285 280 2.64 0.58 bCN(45), bring1(15)

38 _ _ 209 209 2.64 0.43 tbutt(48), tring1(31)

39 _ _ 164 155 1.81 0.37 tring1(72), tring2(12)

Abbreviations used: b, bending; g, deformation; ass, asymmetric; ss, symmetric; t, torsion; sci, scissoring; gHN, twisting. a Relative absorption intensities normalized with highest peak absorption. b Relative Raman intensities calculated and normalized to 100. c For the notations used.

Chemical shifts of the carbon atoms in 4-APP

theoretically are calculated, lies between 105 and 165

ppm. The studies show the chemical shifts calculated

for the hydrogen atoms of amino group are quite low.

The N atom(s) have electronegative property polarizes


page 189 of 232

the electron distribution in its bond to close carbon

atom and lowering the electron density of the

molecule [50].

Table 5. Theoretical isotropic chemical shifts calculated using HF/6-31G* (with respect to TMS, all values in ppm) for 4-aminopyrazolo[3,4-d]pyrimidine [43].

Calculated chemical shift (ppm)

Atom HF/6-31G*

N1 180.7

N2 308.5

C3 134.8

C4 109.2

C5 162.1

N6 248.3

C7 160.2

N8 235.3

C9 157.4

H10 9.1

H11 7.9

N12 78.3

H13 3.6

H14 3.9

H15 8.9

All the exocyclic atoms have atomic charges

corresponds to their electro-negativity while the

charges at all the C atoms of the ring are corresponds

to the net flow of π electrons (delocalization of

electron density) [51]. The Mulliken atomic charges

of every atomic site of 4-APP are gathered in Table 6.

The visible absorption maximum was found to be a

function of electron availability, oscillator strength,

and theoretical electronic excitation energies (as

shown in Table 7).

Depending on the calculated potential energy

distribution results, assignments of the fundamental

vibrational frequencies have been made

unambiguously. The lesser value of HOMO–LUMO

energy gap has essential effect on the intramolecular

bioactivity of the molecule and charge transfer. The

energies of essential MOs and the λmax of the

compounds were also evaluated from TD-DFT

strategy [43].

2.2. 4-Aminopyrazolo[3,4-d]Pyrimidine &

Computational details

One electron excitation from the highest occupied

molecular orbital (HOMO) to the lowest unoccupied

molecular orbital (LUMO) describe the electronic

absorption related to the transition from the ground to

the first excited state.

Table 6. Atomic charges for optimized geometry of 4-APP using DFT B3LYP/6-31G(d,p).

Atomic number 4-APP

Mulliken charges Natural atomic

charges

N1 -0.522 -0.37630

N2 -0.242 -0.25642

C3 -0.002 -0.02723

C4 0.044 -0.24706

C5 0.369 0.45339

N6 -0.480 -0.55445

C7 0.169 0.26115

N8 -0.478 -0.51883

C9 0.554 0.38261

H10 0.350 0.44117

H11 0.153 0.23834

N12 -0.723 -0.82628

H13 0.322 0.40198

H14 0.331 0.40839

H15 0.153 0.21953

Table 7. Theoretical electronic absorption spectra values of 4-APP using TD-DFT/B3LYP/6-31G.

Excited state Wavelength λ (nm) Excitation energies (eV) Oscillator strengths (f)

4-APP 4-APP 4-APP

S1 206.37 6.0079 0.1907

S2 204.00 6.0777 0.1014

S3 187.27 6.6204 0.0082

S4 173.42 7.1494 0.0095

S5 166.95 7.4263 0.0017


page 190 of 232

Table 8. The HOMO–LUMO energy gap of 4-aminopyrazolo(3,4-d)pyrimidine[4AP(3,4-D)P] was calculated at ab initio HF/6−31+G** (d, p) and B3LYP/6−31+G** (d, p)".

Parameters B3LYP/6−311+

G** (d,p) HF/6−311+

G**(d,p)

HOMO energy (a.u.) −0.285697 −0.31699

LUMO energy (a.u.) −0.162230 −0.19304

HOMO–LUMO

energy gap (a.u.)

−0.123467 −0.12395

ab initio HF and density functional methods utilizing

6−31+G (d,p) demonstrate various thermodynamic

properties as heat capacity, zero point energy, entropy

along with the global minimum energy of [4AP(3,4-

D) P]. As shown in Table 9, we present the total

energy and the change in the total entropy of

[4AP(3,4-D)P] at room temperature.

The C–H out-of-plane bending modes were given

within the characteristic region and are shown in

Table 10.

The vibrational properties of 4AP(3,4-d)P have been

investigated by FTIR and Laser Raman spectroscopy

and were performed accordingly to the SQM force

field method based on the ab initio

HF/6−311+G**(d,p) and B3LYP/6−311+G**(d,p)

levels. It was discussed the importance of amino and

other groups in the vibrational frequencies of

4AP(3,4-d)P. The various techniques of vibrations

were unambiguously assigned depend on the results of

the TED output [26].

Figure 2. Atomic orbital (a) HOMO and (b) LUMO compositions of the frontier. Molecular Orbital for pyrazolo(3,4-d)pyrimidine.

Table 9. Thermodynamic parameters of 4-aminoPyrazolo (3,4-d)pyrimidine calculated at HF/6−311+G** (d, p) and B3LYP/6−31+G**(d,p) methods.

Structural parameter Method/basis set

HF/6−311+G**(d,p)

B3LYP/6−311+G**(d,p)

Optimized global minimum

Energy (Hartrees)

−467.6102. −467.4267

Total energy (thermal), Etotal (kcal mol−1 ) 79.822 74.560

Heat capacity, Cv (kcal mol−1 k−1 ) 0.0369 0.0399

Entropy, S (cal mol−1 k−1 ) 26.800 29.023

Total 82.824 84.609

Translational 40.614 40.614

Rotational 28.893 28.951

Vibrational 13.318 15.044

Vibrational energy, Evib (mol−1 k−1 ) 91.859 85.698

Zero point vibrational energy, (Kcal mol−1 ) 75.492 69.927

Rotational constants (GHZ)

A 2.4673 2.4186

B 1.5277 1.4989

C 0.9436 0.9255

Dipole moment (Debye) 2.6914 2.6270


page 191 of 232

Table 10. Vibrational assignments of fundamental frequencies in cm−1 and wave numbers (characterized by TED) obtained for 4-aminoPyrazolo(3,4-d)pyrimidine at HF/6−311+G**(d,p) and B3LYP/6 311+G**(d,p) level: [wave numbers (cm-1); IR intensities (km mol-1); reduced mass (amu), FORCE constant (m dyn A-1); Raman activity (A4/amu)] [26].

S.

no.

Symm

species

Cs

Observed

frequencies

(cm−1 )

B3LYP/6−311+G**(d,p) HF/6−311+G**(d,p) Assignment

(% TED)

FTIR Laser

Raman

Calculated

frequencies

(cm−1 )

IR

Intensity

Raman

activity

Force

constant

Reduced

mass

Calculated

frequencies

(cm−1 )

IR

intensity

Raman

Activity

Force

constant

Reduced

Mass

1 A' 3472(w) – 3730 3.03 46.06 9.051 5.791 3961 5.96 37.36 6.861 7.095 NH2 ass(98)

2 A' – 3406(w) 3661 18.23 130.86 8.539 7.271 3913 25.71 99.45 4.042 9.917 NH2 ss(96)

3 A' 3306 (w) – 3601 509.74 180.33 7.990 8.101 3829 539.33 123.80 9.728 7.454 Ѵ NH(94)

4 A' 3125 (w) – 3229 46.73 34.29 10.868 2.002 3385 60.79 19.96 10.216 4.324 Ѵ CH(92)

5 A' – 3110(w) 3167 113.29 44.74 4.356 2.001 3343 146.89 4.55 9.771 1.432 Ѵ CH(90)

6 A' – 1680(vw) 1651 86.48 32.80 4.724 5.619 1800 162.43 59.30 9.039 6.589 Ѵ NN(89)

7 A' 1674(ms) – 1630 19.09 2.86 1.945 1.377 1794 23.33 84.38 3.133 2.789 NH2

sciss(86)

8 A' – 1610(vw) 1611 0.55 31.11 1.739 4.830 1776 1.45 116.01 2.509 2.553 Ѵ CN(85)

9 A' 1593 (s) – 1508 49.67 14.89 4.499 3.961 1699 58.06 26.41 5.571 6.009 Ѵ CN(84)

10 A' – 1580(w) 1496 33.68 24.80 5.631 1.312 1635 1.62 24.31 7.418 3.617 Ѵ CN(82)

11 A' 1493(ms) 1491(w) 1449 34.37 3.82 2.771 6.446 1585 1.41 25.20 7.201 2.174 Ѵ CN(81)

12 A' – 1478(w) 1399 35.99 14.02 3.255 3.858 1532 53.97 21.48 5.520 5.717 Ѵ CN(82)

13 A' – 1462(w) 1373 1.20 98.01 4.6153 6.946 1481 221.07 0.28 6.144 1.266 Ѵ CN(84)

14 A' – 1394(ms) 1347 12.61 138.17 3.747 2.851 1452 22.44 0.37 3.856 5.619 Ѵ CN(82)

15 A' – 1351(w) 1311 32.98 9.87 3.072 3.527 1398 37.97 16.69 3.975 3.777 Ѵ CC(83)

16 A' 1333(ms) – 1284 9.91 4.56 6.734 5.068 1381 67.5 5.89 2.684 1.365 Ѵ CC(80)

17 A' – 1298(w) 1214 7.48 6.64 6.445 2.591 1291 10.04 6.74 0.819 5.721 Ѵ CC(79)

18 A' 1248(w) – 1166 20.91 9.66 2.908 3.210 1254 34.37 13.09 3.756 3.532 b NH(78)

19 A' 1220(vw) – 1092 113.02 0.47 2.198 3.502 1184 556.26 44.93 5.391 1.099 b CH(76)

20 A' – 1202(vw) 1016 1.54 0.75 2.219 3.027 1129 57.89 3.84 2.202 1.093 b CN(75)

21 A' 1184(vw) – 985 17.56 1.91 2.299 2.664 1107 23.21 8.96 2.628 2.891 b CH(72)

22 A' 1151(vw) 1154(w) 952 195.81 0.13 2.666 3.562 1026 86.95 7.94 3.355 3.901 R symd(70)

23 A' 1075(w) – 905 101.76 8.04 1.147 6.072 986 37.19 0.25 3.545 2.603 Rt rigd(69)

24 A' – 1067(w) 855 16.47 1.06 0.828 2.395 984 21.78 4.74 2.596 2.875 R bend 1(71)

25 A' 1049(w) – 803 55.03 4.53 2.284 8.335 896 260.39 5.55 2.977 3.575 R bend 2(70)

26 A' – 1043(w) 720 26.81 2.16 3.938 1.957 779 5.43 0.94 1.106 6.028 R asymd(78)

27 A' – 1030(w) 694 15.18 0.75 0.605 1.859 769 9.75 1.38 1.385 2.356 NH2

rocking(65)

28 A" 873(w) – 668 222.51 5.59 0.937 1.096 722 28.33 0.28 1.097 4.172 tR symd(63)

29 A" 760(w) – 613 0.26 1.95 1.342 1.091 658 0.93 0.19 1.539 1.773 tR

asymd(64)

30 A" – 724(w) 566 5.89 0.36 0.451 1.811 603 6.17 1.25 0.506 2.283 tR trigd(62)

31 A" – 651(w) 531 25.37 0.11 1.382 3.793 570 12.95 0.32 1.596 3.605 tR bend

1(63)

32 A" 613(w) 615(w) 516 3.75 24.34 0.307 1.886 555 6.69 5.85 0.604 1.473 tR bend


page 192 of 232

2(64)

33 A" 600(w) – 505 5.12 0.33 0.279 1.449 537 3.62 0.75 0.234 1.917 ω CH(61)

34 A" 561(w) – 494 8.16 2.38 0.197 4.278 525 47.76 2.95 0.206 8.327 ω CH(60)

35 A" 544(w) – 293 8.13 0.13 0.244 8.153 315 4.82 0.32 0.329 3.331 ω NH(62)

36 A" – 538(w) 291 5.08 0.17 0.198 1.404 314 3.37 0.36 0.219 1.375 NH2

wagging(59)

37 A" 432(w) – 235 13.63 9.41 0.043 1.104 246 34.82 2.37 0.049 1.105 ω CN(60)

38 A" 354(w) – 202 5.47 5.25 0.155 1.082 217 3.71 2.57 0.159 1.083 NH2

twisting(59)

39 A" 129(w) – 154 3.51 0.11 0.054 1.046 174 3.07 0.99 0.063 1.047 Butterfly(58)

2.3. Synthesis of 1- and 2-aryl-pyrazolo[4,3-

d]pyrimidine 2, 1- and 2-aryl-pyrazolo[3,4-

d]pyrimidine

Scheme 2. pyrazolo[3,4-d]pyrimidine derivatives

2.3.1. Computational details

The system uses the B3LYP /6-31G (d) [35]

computational level. Relatively the calculations, the

molecules with minimum energy where λ is the

number of negative eigenvalues of the Hessian matrix

for a given stationary point) on the Potential Energy

Surface.

It was found, that the Relative energies (kJ/mol) of

isomers, classified by families (without aza, monoaza,

diaza and triaza). Relative energy minima in bold (the

compounds of only an isomer calculated have no

reltive energy value). The negative values of the last

column mean that a are more stable than b.

Table 11. Relative energy of isomers (Kj/mol)

Compound Isomer a Isomer b a vs. B

2 (diaza-4,6) 21.5 1.9 -22.3

3 (diaza-5,7) 0.0 0.0 -41.8

The geometries of compounds in the solid state it is

useful to use theoretical calculations in the gas phase.

This allows to have a complete set of related

structures and to differentiate the intrinsic effects from

crystal field ones [52-55].

None the less , from the present survey, several

conclusions can be drawn: i) N internal angles are

more reliable than NC distances for structural

characterization; ii) 1- and 2-aryl series form two

separated sets; iii) a rationale has been found for the

N-aryl torsion angles [56].

2.4. Synthesis of 4-Alkylidenehydrazino-1H-

pyrazolo[3,4-d]pyrimidines and arylmethylidene

hydrazino-1H-pyrazolo[3,4-d]pyrimidines

4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidin-

es, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]-

pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-

1,2,4-triazolo-[1,5-c]-pyrimidines as potential

xanthine oxidase inhibitors were docked into the

active site of the bovine milk xanthine dehydrogenase

using two scoring functions involved in the CAChe

6.1.10 and Auto Dock 3.05.

Through the docking investigation into the active site

of XDH (PDB codes it was obtained Structures of

different bicyclic pyrazolo pyrimidines 4–6 and

tricyclic Pyrazolo triazolo pyrimidines 7a–s.

Figure 3. b) and log IC50 of allopurinol, oxipurinol, 6b, e–k, m–r, and 7a–s docked against XDH (1n5x)".


page 193 of 232

Scheme 3. Structure of pyrazolo[3,4-d]pyrimidine derivatives

Table 12. The best docking results based on the binding free energies (ΔGb) of the compounds docked against XDH (PDB code: 1n5x), the distance and angle of hydrogen bonds between compounds and amino acid residues involved in XDH, and RMSD from the crystallized TEI- 6720 ligand [57].

Compound IC50 (µM)a b (kcal/mol)b Hydrogen bonds between atoms of compounds and amino acids RMSD (A°)d

Atom of compound Amino acid Distance (A° ) Angle ( )

Allopurinol 24.3 -7.39 N8–N HN of Thr 1010 2.05 167.0 5.55

C6–OH OE2 of Glu 802 2.17 155.5

Oxipurinol 22.1 -7.54 C2–Oxo HO of Ser 876 2.31 146.7 3.93

C6–Oxo HN of Thr 1010 2.06 135.4

C6–Oxo Hn(HH22) of Arg 880 1.76 162.8

6a –d -7.72 C6–Oxo HN of Thr 1010 2.08 136.6 5.05


page 194 of 232

C6–Oxo HN(HH22) of Arg 880 1.87 151.3

6b 4.670 -8.07 N7–H OH of Thr 1010 2.19 138.9 3.90

C6–Oxo HN(HH22) of Arg 880 1.71 146.1

6c – -8.53 C6–Oxo HN(HH22) of Arg 880 1.72 141.5 4.38

6d – -9.23 N2–N HE of Arg 880 1.99 138.0 4.86

N2–N HH22 of Arg 880 1.72 145.8

6f 7.894 -9.34 C6–Oxo HN of Ala 1079 2.21 164.6 2.14

6g 0.305 -9.88 N2–N HN(HE) of Arg 880 2.27 135.9 4.83

N2–N HN(HH22) of Arg 880 1.67 159.1

N1–H OH of Thr 1010 1.84 147.2

6h 0.373 -9.35 N2–N HN Ala 1079 2.07 145.9 2.86

C4–NH OE1 of Glu 802 1.86 136.1

C6–Oxo HN(HH22) of Arg 880 2.03 157.7

C6–Oxo HN of Thr 1010 1.90 141.1

6i 0.077 -9.79 C6–Oxo HN of Thr 1010 2.05 137.3 3.08

C6–Oxo HN(HH22) of Arg 880 1.87 153.8

N2–N HN of Ala 1079 2.19 148.8

6j 0.223 -9.35 N2–N HN Ala 1079 2.27 147.5 3.10

C6–Oxo HN(HH22) of Arg 880 1.83 150.8

6k 0.224 -9.55 N2–N HN Ala 1079 2.22 143.4 2.93

C6–Oxo HN(HH22) of Arg 880 2.06 155.3

C6–Oxo HN of Thr 1010 1.92 141.5

6le >10 -10.39 C6–Oxo HN of Thr 1010 1.94 138.4 3.09

C6–Oxo HN(HH22) of Arg 880 1.91 162.1

C1–N HN of Ala 1079 2.26 147.0

6m 0.247 -10.34 C6–Oxo HN of Thr 1010 1.96 140.0 2.95

C6–Oxo HN(HH22) of Arg 880 1.96 158.9

C4–NH OE1 of Glu 802 1.74 137.7

N2–N HN of Ala 1079 2.24 146.4

6n 0.172 -9.91 C6–Oxo HN of Thr 1010 2.03 162.6 2.94


page 195 of 232

C6–Oxo HN(HH22) of Arg 880 2.05 154.7

6o 0.385 -10.96 C6–Oxo HN of Thr 1010 2.08 143.0 3.04

C6–Oxo HN(HH22) of Arg 880 2.07 152.8

N2–N HN of Ala 1079 1.97 144.6

6p 0.399 -10.55 p–COO HN(HZ1) of Lys 771 1.99 145.2 2.14

C6–Oxo HN(HH22) of Arg 880 1.92 171.0

N2–N HN of Ala 1079 2.23 152.6

6q 0.359 -9.81 C6–Oxo HN of Thr 1010 2.07 143.4 2.82

C6–Oxo HN(HH22) of Arg 880 2.13 150.8

6r 1.925 -10.23 p–N=O HN(HE) of Arg 880 2.14 137.5 1.21

p–N=O HN(HH22) of Arg 880 2.49 139.1

p–N=O HN of Thr 1010 1.71 155.1

p_N+_O- HN(HH22) of Arg 880

6s – -11.85 C6–Oxo HN of Thr 1010 1.88 143.2 2.16

C6–Oxo HN(HH22) of Arg 880 2.12 156.3

N2–N HN of Ala 1079 2.07 143.1

7a 0.184 -8.86 C5–Oxo HH22 of Arg 880 1.85 158.2 5.59

7b 0.250 -9.40 C5–Oxo C5–Oxo HN of Thr 1010 1.96 138.2 5.35

HN(HH22) of Arg 880 1.90 158.6

7c 0.782 -9.33 C5–Oxo HN(HH22) of Arg 880 1.77 153.5 4.82

N8–N HN of Ala 1079 2.24 147.0

7d 0.529 -10.15 C5–Oxo HN(HH22) of Arg 1.83 138.2 4.32

N6–H OH of Thr 1010 1.85 149.9

7e 0.069 -10.84 C5–Oxo HN(HH22) of Arg 880 1.67 152.3 3.49

N8–N HN of Ala 1079 2.33 146.7

7f 0.117 -11.11 C5–Oxo HN(HH22) of Arg 880 1.87 136.2 2.27

N8–N HN of Ala 1079 1.93 145.8

7g 0.103 -10.53 C5–Oxo HN of Thr 1010 1.95 139.8 3.92

C5–Oxo HN(HH22) of Arg 880 1.95 159.9

N8–N HN of Ala 1079 2.44 146.4


page 196 of 232

7h 0.062 -10.68 C5–Oxo HN of Thr 1010 1.96 142.9 3.58

C5–Oxo HN(HH22) of Arg 880 2.06 158.4

7i 0.070 -10.90 C5–Oxo HN of Thr 1010 1.95 140.7 3.75

C5–Oxo HN(HH22) of Arg 880 1.98 160.8

7j 0.038 -11.21 C5–Oxo HN of Thr 1010 1.94 142.5 3.62

C5–Oxo HN(HH22) of Arg 880 2.05 158.6

7k 0.032 -10.97 C5–Oxo HN of Thr 1010 1.99 142.1 3.54

C5–Oxo HN(HH22) of Arg 880 2.04 155.7

7l 0.034 -11.08 C5–Oxo HN of Thr 1010 1.99 140.8 3.55

C5–Oxo HN(HH22) of Arg 880 1.98 156.7

N8–N HN of Ala 1079 2.28 146.5

7m 0.041 -10.98 C5–Oxo HN of Thr 1010 2.00 141.6 3.55

C5–Oxo HN(HH22) of Arg 880 2.02 155.7

N8–N HN of Ala 1079 2.23 146.3

7n 0.053 -10.60 C5–Oxo HN of Thr 1010 1.98 141.9 3.23

C5–Oxo HN(HH22) of Arg 880 2.03 156.4

N8–N HN of Ala 1079 2.27 146.0

7o 0.041 -10.89 C5–Oxo HN of Arg Thr 1010 1.97 144.1 2.88

C5–Oxo HN(HH22) of Arg 2.03 157.3

7q 0.055 -10.49 C5–Oxo HN of Arg Thr 1010 1.98 141.4 3.26

C5–Oxo HN(HH22) of Arg 880 2.01 156.5

N8–N HN of Ala 1079 2.29 146.1

7r 0.060 -11.19 C5–Oxo HN of Thr 1010 1.89 142.8 2.52

C5–Oxo HN(HH22) of Arg 880 2.06 161.4

N8–N HN of Ala 1079 2.34 145.4

7s 0.037 -11.78 N5–H OH of Thr 1010 1.75 140.7 1.30

a Through reference . b Binding free energy. c Root mean square deviation. d Not determined. e This value is inaccurate because of the insolubility in DMSO.

2.5. Pyrazolo[3,4-d]pyrimidines

Pyrazolo[3,4-d]pyrimidines have a class of naturally

occurring fused uracils that appear diverse biological

activities. Through each method, Docking results

make obvious that Pyrazolo[3,4-d]pyrimidine

molecules with trimethylene linker can bond to both

anti-coagulation and enzymatic regions of

Phospholipase A2 (PLA2) [16]. The pyrazolo[3,4-


page 197 of 232

d]pyrimidine molecules considered for docking

studies are 1,3-bis(4,6-diethylthio-1H-pyrazolo[3,4-

d]pyrimidin-1-yl)propane [58] 8; 1,3-bis(4-ethoxy-6-

methyl-sulfanyl-1H-pyrazolo[3,4-d] pyrimidin-1-

yl)propane 9 [59]; 1,10-(1,3-propanediyl)bis(5-

methyl-6-methylthio-4,5-Pyrazolo[3,4-d]pyrimidines

as inhib-itor of viper Phospholipase A2 421 dihydro-

1H-pyrazolo[3,4-d]pyrimidin-4-one) 10 [60]; 1,10-

(1,3-propanediyl)bis(5-ethyl-6-methylthio-4,5-

dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one) 11 [61];

1,10-(1,3- propanediyl)bis(5-benzyl-6-methylsulfanyl-

4,5-dihy-dro-1H-pyrazolo[3,4-d]pyrimidin-4-one) 12

[62]; 1-(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-

d]pyrimidin-1-yl)-3-(5-methyl-6-methylsulfanyl-4-

oxo-1,5-dihydropyra-zolo[3,4-d]pyrimidin-1-yl)prop-

ane 13 [63]; 4,6-bis(methylsulfanyl)-1-

phthalimidopropyl-1H-pyrazo-lo[3,4-d]-pyrimidine 14

[64]; 6-methylsulfanyl-1-phthalimidopropyl-

4(pyrrolidin-1-yl)-1H-pyrazolo-[3,4-d]pyrimidine 15

[64]; and 6-methylsulfanyl-1-(3-phenylpropyl)-4,5-

dihydro-1H-pyrazolo[3,4-d]pyrimidine-4-one 16 [65].


The Conformational search and docking studies using

AUTODOCK4.2 show that electronic interaction has

an important role in ligand–channel interaction. Table

13 show the result. For the best degree of the docked

poses, with comparable to the indomethacin binding

to PLA2, molecules 8, 9, 11 and 13 have poor binding

energies., molecule 15 has the comparable energy

while molecules 10, 12, 14 and 16 have better bound

energy values.

Scheme 4. Chemical diagram of ligands (molecules 8–16 and IMN)".


page 198 of 232

Table 13. Inhibition coefficient (KI) and different energy values of the ligands as obtained through the docking with 3H1X using AUTODOCK4.2.

Molecules Rank Kl (μM) Intramolecular

energy

(kcal/mol)

Internal

energy

(kcal/mol)

Torsional

energy

(kcal/mol)

Binding

Energy

(kcal/mol)

8 1-1 74.69 −9.21 0.19 3.58 −5.63

2-1 131.66 −8.87 −0.83 3.58 −5.29

3-1 160.42 −8.76 −0.55 3.58 −5.18

3-2 388.60 −8.23 −0.60 3.58 −4.65

4-1 249.63 −8.49 −0.80 3.58 −4.91

9 1-1 290.50 −7.80 −0.59 2.98 −4.83

2-1 295.25 −7.80 −0.23 2.98 −4.82

3-1 368.95 −7.67 −0.35 2.98 −4.68

3-2 375.14 −7.66 −0.66 2.98 −4.67

4-1 504.85 −7.48 −0.70 2.98 −4.50

10 1-1 9.21 −8.66 −0.12 1.79 −6.87

1-2 10.95 −8.56 −0.14 1.79 −6.77

1-3 20.45 −8.19 −0.20 1.79 −6.40

2-1 10.76 −8.57 0.30 1.79 −6.78

2-2 32.88 −7.91 −0.25 1.79 −6.12

11 1-1 91.64 −7.90 −0.50 2.39 −5.51

2-1 115.41 −7.76 −0.54 2.39 −5.37

2-2 178.43 −7.50 −0.25 2.39 −5.11

3-1 233.02 −7.34 −0.49 2.39 −4.96

4-1 282.48 −7.23 −0.73 2.39 −4.84

12 1-1 18.62 −9.44 −0.74 2.98 −6.45

2-1 34.87 −9.06 −1.44 2.98 −6.08

3-1 79.36 −8.58 −1.11 2.98 −5.59

4-1 84.09 −8.54 −1.29 2.98 −5.56

5-1 142.00 −8.23 −1.11 2.98 −5.25

13 1-1 81.41 −7.67 −0.18 2.09 −5.58

2-1 333.24 −6.83 −0.88 2.09 −4.74

3-1 349.47 −6.80 −0.61 2.09 −4.72

4-1 456.35 −6.65 −0.16 2.09 −4.56

5-1 480.47 −6.62 −0.60 2.09 −4.53

14 1-1 8.56 −8.70 −0.29 1.79 −6.91

1-2 11.47 −8.53 −0.31 1.79 −6.74

1-3 13.87 −8.42 −0.15 1.79 −6.63

2-1 69.00 −7.47 −0.38 1.79 −5.68

3-1 74.44 −7.42 −1.23 1.79 −5.63

15 1-1 27.26 −8.02 −0.63 1.79 −6.23

1-2 38.61 −7.81 −0.82 1.79 −6.02

2-1 118.32 −7.15 −1.50 1.79 −5.36

3-1 128.14 −7.10 −1.36 1.79 −5.31

4-1 171.61 −6.93 −1.29 1.79 −5.14


page 199 of 232

16 1-1 13.88 −8.12 −0.6 1.49 −6.63

2-1 45.30 −7.42 −0.32 1.49 −5.93

2-2 58.17 −7.27 −0.32 1.49 −5.78

3-1 51.53 −7.34 −0.51 1.49 −5.85

3-2 58.36 −7.27 −0.48 1.49 −5.78

IMN 1-1 22.90 −7.52 −0.66 1.19 −6.33

2-1 24.65 −7.48 −0.70 1.19 −6.29

2-2 27.00 −7.43 −0.68 1.19 −6.23

3-1 27.26 −7.42 −0.66 1.19 −6.23

3-2 32.31 −7.32 −0.69 1.19 −6.13

Table 14. Glide scores and average electrostatic (coul), van der Waals (vdw), site energy (site) and Glide energy obtained through Glide SP docking.

Molecules

(SP)

Entry

ID

Glide

score

Ecoul

(kcal/mol)

Evdw

(kcal/mol)

Esite

(kcal/mol)

Glide

energy

(kcal/mol)

8 32 −5.565 −3.270 −48.226 −0.157 −51.496

40 −5.367 −0.968 −49.591 −0.167 −50.559

44 −5.307 −2.830 −48.543 −0.185 −51.372

47 −5.247 −2.134 −49.201 −0.180 −51.335

56 −5.187 −1.967 −48.731 −0.183 −50.698

9 69 −4.856 −2.183 −43.014 −0.163 −45.197

76 −4.791 −3.310 −42.334 −0.193 −45.644

86 −4.694 −2.842 −42.245 −0.204 −45.087

93 −4.565 −3.323 −44.350 −0.142 −47.673

110 −4.073 −4.202 −43.388 −0.170 −47.589

10 8 −6.417 −4.752 −48.490 −0.017 −53.243

13 −5.887 −5.426 −47.934 −0.111 −53.360

14 −5.884 −5.442 −47.828 −0.017 −53.270

24 −5.787 −5.894 −43.697 −0.091 −49.592

25 −5.757 −5.637 −44.583 −0.090 −50.221

11 2 −6.705 −4.248 −50.535 −0.010 −54.783

3 −6.688 −4.189 −50.629 −0.010 −54.819

4 −6.668 −4.200 −50.783 −0.012 −54.983

5 −6.493 −4.304 −50.249 −0.010 −54.554

6 −6.435 −0.814 −52.373 0.0000 −53.187

12 89 −4.636 −2.338 −46.642 0.000 −48.980

100 −4.318 −7.057 −42.092 −0.042 −49.149

102 −4.283 −2.417 −43.022 −0.046 −45.439

103 −4.273 −3.476 −42.849 −0.002 −46.325

105 −4.216 −6.989 −39.835 −0.045 −46.823

13 7 −6.433 −1.882 −52.926 0.0000 −54.809

36 −5.429 −3.008 −43.402 −0.162 −46.410

37 −5.420 −2.630 −43.489 −0.173 −46.119

38 −5.392 −2.871 −43.764 −0.177 −46.635


page 200 of 232

42 −5.380 −3.307 −41.347 −0.168 −44.655

14 17 −5.822 −3.086 −44.766 −0.018 −47.852

19 −5.818 −2.983 −45.060 −0.018 −48.043

20 −5.817 −2.871 −45.000 −0.017 −47.872

21 −5.815 −2.970 −45.107 −0.018 −48.077

22 −5.812 −2.854 −45.048 −0.017 −47.902

15 15 −5.866 −2.921 −46.758 −0.017 −49.679

34 −5.489 −1.316 −44.899 −0.043 −46.215

92 −4.591 −0.780 −41.055 −0.029 −41.836

94 −4.543 −1.039 −41.186 −0.045 −42.225

97 −4.396 −0.641 −40.911 −0.032 −41.553

16 71 −4.828 −3.552 −31.002 0.000 −34.554

74 −4.819 −3.611 −30.910 0.000 −34.521

75 −4.809 −3.538 −30.922 0.000 −34.460

77 −4.786 −3.340 −31.093 0.000 −34.432

78 −4.776 −3.606 −30.638 0.000 −34.244

IMN 84 −4.709 −8.409 −24.405 −0.087 −32.814

87 −4.672 −8.357 −24.488 −0.088 −32.846

111 −4.064 −6.586 −21.505 −0.100 −28.091

121 −3.243 −5.559 −23.459 −0.100 −29.018

In Table 14, the results of Glide docking in Standard

Precision mode are summarized. Docking of

Pyrazolo[3, 4-d]pyrimidine ligands and IMN appeared

a great variation in their binding energy.

From Autodock calculations, it was noted that

molecules 10, 12, 14 and 16 have better binding

capabilities and minimum inhibitory concentrations

than indomethacin. almost all the Pyrazolo[3,4-

d]pyrimidine molecules have better binding energies

than indomethacin by obtaining Docking simulations

through Standard Precision and Extra Precision

protocols of Glide [16].

2.6. Synthesis of pyrazolo[3,4-d]pyrimidine

derivatives

By using the density functional B3LYP/6-31G** and

dispersion corrected density functional DFT-D/B97D

methods, the conformational stabilities and

computations of optimized geometrical parameters of

1,3-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-

1-yl)propane 18; 1,3-bis(4-ethoxy-6-methylsulfanyl-

1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane 19; 4,6-

bis(methylsulfanyl)-1-phthalimidopropyl-1H-

pyrazolo[3,4-d]pyrimidine 20 and 6-methylsulfanyl-

1-phthalimidopropyl-4(pyrollidin-1-yl)-1H-

pyrazolo[3,4-d]pyrimidine 21 molecules have been

detected.

Geometries at the minimum energies were fully

optimized without any constraints. Since B3LYP

method does not include the dispersion term, M06-

2X/6-311++G** method is used to define the energies

of the B3LYP optimized geometries, which is known

to better convenient for non-covalent interactions.

Figure 4. Chemical Structures with atomic numbering scheme of molecules 18, 19, 20 and 21. (Hydrogen atoms have been omitted for clarity. Torsion angles chosen for conformational variations are N1-C8-C9-C10 (τ1) and C8-C9-C10-N11 (τ2).


Figures (5,6) show molecular structures function of

lowest energy conformation of all the four studied

compounds and this conformation is a folded one

donating ample scope for arene–arene (aromatic Π–Π)

interactions.


page 201 of 232

Table 15a. Total energies (E), relative energies (ΔE) and torsion angles (τ1, τ2) corresponding to different conformations of molecule 18. The crystallographic value of torsion angles are (-52.26, -52.26o).

Conf.

(mol.18)

E (Hartree) ΔE (kcal/mol) τ 1 τ 2

B3LYP M06-2X B97D B3LYP M06-2X B97D B3LYP/M06-2X B97D B3LYP/M06-2X B97D

I -2847.8947 -2847.67026 -2847.0021 0.02 4.78 7.26 66.6 62.0 176.9 186.2

II -2847.8946 -2847.67008 -2847.0020 0.04 4.89 7.29 177.3 -173.1 67.7 61.7

III -2847.8935 -2847.66981 -2846.9958 0.73 5.06 11.18 -179.5 -172.7 -65.7 -60.1

IV -2847.8935 -2847.66968 -2846.9958 0.75 5.14 11.15 -66.6 -61.4 179.4 186.4

V -2847.8947 -2847.67787 -2847.0136 0.00 0.00 0.00 -56.7 -49.4 -56.5 -49.5

Table 15b. Total energies (E), relative energies (ΔE) and torsion angles (τ1, τ2) corresponding to different conformations of molecule 19. The crystallographic value of torsion angles is (47.9o, 54.2o).

Conf.

(mol.19)


B3LYP M06-2X B97D B3LYP M06-

2X

B97D B3LYP/M06-

2X

B97D B3LYP/M06-

2X

B97D

I -2123.3325 -2123.13605 -2122.4071 21.13 5.49 11.63 66.0 56.3 179.8 166.5

II -2123.3325 -2123.13610 -2122.4071 21.13 5.45 11.63 179.7 167.2 66.0 57.0

III -2123.3662 -2123.13637 -2122.4116 0.00 6.97 8.75 183.3 171.9 -66.9 -63.2

IV -2123.3662 -2123.13635 -2122.4117 0.00 5.29 8.73 -66.9 -62.6 -176.5 172.1

V -2123.3335 -2123.14479 -2122.4256 20.51 0.00 0.00 54.0 49.1 54.4 48.6

Table 15c. Total energies (E), relative energies (ΔE) and torsion angles (τ1, τ2) corresponding to different conformations of molecule 20.The crystallographic value of torsion angles are (167.3o, 69.8o).

Conf.

(mol. 20)



2X

B97D B3LYP/M06-

2X

B97D B3LYP/M06-

2X

B97D

I -1916.7796 -1916.62037 -1915.9895 0.08 0.58 8.82 67.1 62.4 177.2 -174.7

II -1916.7801 -1916.62129 -1915.9936 0.00 0.00 6.27 177.0 -162.8 66.6 68.4

III -1916.7795 -1916.62078 -1916.0036 0.17 0.27 0.00 179.4 55.3 -66.9 -80.3

IV -1916.7793 -1916.62104 -1915.9901 0.28 0.16 8.45 -64.8 -61.9 -176.9 -175.7

V -1916.7797 -1916.62118 -1916.0007 0.01 0.07 1.84 -57.9 -49.1 -58.4 -49.5

Table 15d. Total energies (E), relative energies (ΔE) and torsion angles (τ1, τ2) corresponding to different conformations of molecule 21. The crystallographic value of torsion angles are (67.3o, 169.3o).

Conf.

(mol.21)



2X

B97D B3LYP/M06-

2X

B97D B3LYP/M06-2X B97D

I -1690.6875 -1690.50018 -1689.7786 15.50 1.08 6.92 67.2 63.3 178.9 184.9

II -1690.6873 -1690.50047 -1689.7808 15.63 0.90 5.56 177.3 -147.3 65.9 68.6

III -1690.6868 -1690.50004 -1689.7779 15.90 1.17 7.38 177.7 179.3 -68.5 -64.5

IV -1690.6873 -1690.50081 -1689.7790 15.65 0.68 6.66 -65.8 -62.8 178.3 179.8

V -1690.7122 -1690.50190 -1689.7897 0.00 0.00 0.00 -64.8 -70.1 75.6 65.5


page 202 of 232

Figure 5. Different conformers of the molecules obtained from B3LYP/6-31G** method.

Figure 6. Different conformers of the molecules obtained from DFT-D/B97D method.


page 203 of 232

Table 16. Comparison of crystallographic and theoretical values (obtained from B3LYP and B97D methods) of some selected torsion angles of molecule 21 in different conformers

Torsions Conformers

Cyst. Values B3LYP B97D

I II III IV V I II III IV V

N1-C8-C9-C10 (τ 1) 67.3(4) 67.2 177.3 177.7 -65.8 -64.8 63.3 -147.3 179.2 -62.8 -70.1

C8-C9-C10-N11 (τ2) 169.3(3) 178.9 65.9 -68.5 178.3 75.6 184.9 68.6 -64.5 179.8 65.5

N5-C4-N18-C19 176.1(3) 177.2 175.8 176.3 176.9 177.6 177.6 176.6 176.9 177.3 176.2

C4-N18-C19-C20 -165.7(4) -170.2 -168.2 -168.7 -169.5 -170.3 -170.1 -169.0 -169.4 -169.4 -170.3

N18-C19-C20-C21 -13.5(6) -29.1 -29.1 -29.2 -29.3 -29.0 -30.1 -29.9 -30.0 -30.3 -29.6

N5-C4-N18-C22 4.5(4) -3.0 -2.4 -2.6 -3.0 -2.8 -3.2 -2.6 -2.9 -2.9 -4.1

C19-C20-C21-C22 15.5(7) 37.4 37.4 37.4 37.4 37.3 38.5 38.6 38.6 38.7 38.4

C20-C21-C22-N18 -10.7(6) -30.9 -30.9 -30.8 -30.8 -30.8 -31.7 -31.9 -31.9 -31.7 -31.9

C21-C22-N18-C19 1.8(4) 13.2 13.1 13.0 12.9 13.1 13.4 13.8 13.7 13.3 13.9

C21-C22-N18-C4 174.3(3) -166.7 -168.5 -167.9 -167.2 -166.5 -165.9 -166.9 -166.6 -166.5 -165.8

C22-N18-C19-C20 6.7(4) 10.1 10.1 10.3 10.4 10.1 10.6 10.2 10.4 10.8 9.9

Table 17. Substituions of pyrazolo[3,4-d]pyrimidine


page 204 of 232

Different theoretical strategies have exhibited that all

the four pyrazolo[3,4-d]pyrimidine derivatives have

five theoretically possible stable conformers of about

equivalent energies.

For molecule, both theoretical methods B3LYP and

B97D, utilized to examine the conformational

preferences, do not agree consistently while

distinguishing the global minimum.

The ᴨ-ᴨ interaction energy in the state of molecules

18 and 19 has values 4.78 kcal/mol and 5.49 kcal/mol

respectively. In instances of molecules 20 and 21 all

the conformers are practically broadened and have

approximately same energy which indicates that

intermolecular ᴨ-ᴨ interaction is missing in these

particles [66].

2.7. Synthesis of 1-(2-ethoxyethyl)-1H-pyrazolo[4,3-

d]pyrimidines

Phosphodiesterase V works as an appealing target for

cardiovascular, Quantitative Structure–Activity

Relationship (QSAR) consider as useful procedure for

the optimization of structure necessities of twenty-six

1-(2-ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as

phosphodiesterase V inhibitors.

2.7.1. The structural template of 1-(2-ethoxyethyl)-

1H-pyrazolo[4,3-d]pyrimidine

Scheme 5. 1-(2-ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines structure

Various quantum chemical methods and quantum-

chemistry calculations have been performed for

studying the molecular structure and electronic 1-(2-

ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidine derivate-

ives properties [67,68]. The properties of biological

Activity of organic compounds related to the

geometry and additionally the nature of their

molecular orbital, HOMO (highest occupied

molecular orbital) and LUMO (lowest unoccupied

molecular orbital). In the next Table (Table 19), we summarized The

Pearson correlation coefficients. The obtained matrix

provides Information on the negative or positive

correlation between variables.

Table 18. Values of the calculated parameters obtained by DFT/B3LYP 6-31G* optimization and ACD/ChemSketch program of the studied compounds.

N0 pIC50

MW

MR

(cm3)

MV

(cm3)

Pc

(cm3)

n

αe

(dyne

/cm)

D (g/

cm3)

ET

(ua)

EHomo

(ev)

ELum

o

(ev)

∆E

(ev)

µ

(D)

Ea

(ev)

λmax

(nm)

f(so)

22 a 1,155

395,5

113,33

306,3

817,1

1,661

50,6

1,29

-34750

-5,096

-1,09

4,006

2,48

2,214

560,1

0,0139

22 b 0,398 382,46 107,17 278,8 759,7 1,694 55 1,37 -33052,9 -5,511 -1,58 3,935 2,53 3,499 354,4 0,0024

22 c 1,155 396,49 111,77 294,9 798,3 1,682 53,6 1,34 -35186,6 -5,007 -1,07 3,934 3,53 2,149 576,8 0,0134

22 d 0,187 396,49 111,59 294 790,8 1,683 52,3 1,34 -35194,8 -5,141 -1,24 3,903 3,86 3,072 403,6 0,0244

22 e 0,18 410,52 116,2 310,1 829,4 1,672 51,1 1,32 -36257,6 -5,195 -1,22 3,975 1,30 3,472 357,1 0,0006

22 f -0,146 396,49 111,59 294 790,8 1,683 52,3 1,34 -35194,6 -5,189 -1,31 3,881 5,29 3,561 348,2 0,002

22 g 0,420 410,52 116,2 310,1 829,4 1,672 51,1 1,32 -36265,3 -5,202 -1,32 3,881 5,38 3,065 404,6 0,0216

22 h -0,519 410,52 116,2 310,1 829,4 1,672 51,1 1,32 -36257,5 -5,182 -1,22 3,964 2,8 2,112 587,1 0,0156

22 i -0,74 410,52 116,2 310,1 829,4 1,672 51,1 1,32 -36257,5 -5,005 -0,98 4,028 2,34 3,253 381,2 0,0694

22 j -0,415 410,51 116,92 315,3 836,2 1,663 49,4 1,3 -36257,7 -5,004 -1,08 3,926 4,43 3,554 348,8 0,0021

22 k 0,051 424,54 121,52 331,3 874,8 1,654 48,5 1,28 -37328,2 -5,21 -1,25 3,957 1,89 2,761 449,1 0,0083

22 l -0,398 424,54 120,62 325,2 860,5 1,663 48,9 1,30 -37328,4 -5,153 -1,21 3,942 1,40 3,494 354,8 0,0024

22 m -0,079 424,54 120,62 325,2 860,5 1,663 48,9 1,30 -37328 -4,904 -0,96 3,939 4,73 3,549 349,3 0,006

22 n 0,119 424,54 120,81 326,1 868 1,662 50,1 1,30 -37328,1 -4,915 -1,09 3,825 4,01 3,406 364,0 0,0577

22 o 0,699 424,54 119,91 320 853,6 1,672 50,6 1,32 -37328,1 -5,213 -1,25 3,964 2,41 3,384 366,4 0,0611

22 p 0,143 438,57 125,23 341,3 899,1 1,654 48,1 1,28 -38398,6 -5,059 -1,05 4,013 4,44 3,221 384,9 0,0236

22 q 1,060 452,6 130,56 362,5 944,5 1,639 46 1,24 -39468,7 -4,900 -0,99 3,91 4,79 2,633 470,8 0,0055

22 r 0,377 424,54 120,62 325,2 860,5 1,663 48,9 1,30 -36257,9 -5,028 -1,09 3,94 5,6 3,737 331,8 0,0463

22 s -0,362 410,52 115,06 302,1 816,8 1,686 53,3 1,35 -36257,9 -5,028 -1,09 3,94 5,6 3,452 359,2 0,0032


page 205 of 232

22 t 0,108 424,54 119,67 318,2 855,4 1,675 52,2 1,33 -37328,4 -5,008 -1,09 3,916 3,48 3,742 331,4 0,0754

22 u 0,456 424,54 119,91 320 853,6 1,672 50,6 1,32 -37328,1 -5,038 -1,07 3,97 4,77 3,326 372,8 0,0545

22 v 1,155 424,54 119,67 318,2 855,4 1,675 52,2 1,33 -37310,3 -4,846 -1,00 3,843 4,08 3,754 330,3 0,062

22 w -0,079 411,5 113,63 305,8 814,4 1,665 50,3 1,34 -36798,6 -5,112 -1,12 3,996 3,55 4,051 306,1 0,0659

22 x 1,155 439,55 123,21 334,7 892,5 1,657 50,5 1,31 -38948 -5,092 -1,28 3,812 5,27 3,448 359,6 0,0635

22 y 1,097 452,55 125,13 331,5 899,7 1,679 54,2 1,36 -40414,7 -4,859 -0,92 3,939 5,85 1,932 641,7 0,0078

22 z 1,398 453,54 124,07 332 898,2 1,67 53,5 1,36 -40956,1 -5,079 -1,12 3,956 5,43 3,319 373,6 0,0197

Table 19. Correlation matrix (Pearson (n)) between different obtained descriptors:

pIC50 MW MR MV Pc N αe D ET EHOMO ELUMO E µ Ea λmax f(so)

pIC50 1

MW 0,367 1

MR 0,301 0,962 1

MV 0,270 0,917 0,984 1

Pc 0,344 0,962 0,995 0,987 1

N -0,096 -0,577 -0,720 -0,831 -0,746 1

0,197 -0,360 -0,555 -0,674 -0,547 0,905 1

D 0,059 -0,317 -0,547 -0,668 -0,551 0,898 0,942 1

ET -0,374 -0,974 -0,897 -0,843 -0,904 0,496 0,246 0,194 1

EHOMO 0,192 0,546 0,563 0,532 0,556 -0,342 -0,235 -0,271

-0,540 1

ELUMO 0,088 0,504 0,523 0,503 0,515 -0,355 -0,273 -0,284

-0,501

0,928

1

E -0,273 -0,110 -0,104 -0,077 -0,107 -0,036 -0,098 -0,035

0,101

-0,189

0,191 1

µ 0,292 0,392 0,306 0,245 0,298 0,007 0,097 0,134

-0,397

0,452

0,300 -0,400 1

Ea -0,311 -0,047 -0,085 -0,084 -0,115 0,047 -0,103 0,104

0,082

-0,092

-0,161 -0,180 0,053 1

Λmax 0,317 0,046 0,061 0,051 0,091 0,001 0,161 -0,029

-0,087

0,134

0,204 0,184 -0,031 -0,984 1

f(so) 0,070 0,169 0,126 0,110 0,125 -0,068 -0,026 0,045

-0,151

0,241

0,190 -0,132 0,021 0,400 -0,365 1

The Energy of activation Ea is negatively correlated

with the maximum of absorption λ max (r = -0.984 and

p <0.05) at a significant level.

The Density D is correlated positively with the surface

tension αe (r =0.942 and p< 0.001) at a significant

level. The analysis of projections is according to the

planes F1–F2 and F1-F3 (59.53% and 58.28% of the

total variance respectively) of the studied molecules

[69].

2.8. Synthesis of 3-phenyl-1-tosyl-1H-pyrazolo[3,4-

d]pyrimidin-4-amine

Using Hartree Fock (HF/6-31G**) and density

functional theory (B3LYP/6-31G**) techniques to

obtain the electronic structure calculations and

vibrational assignments of a biologically important

molecule namely, 3- phenyl-1-tosyl-1H-pyrazolo[3,4-

d]pyrimidin-4-amine. The optimized geometrical

parameters, molecular electrostatic potentials (MEP),

and HOMO–LUMO gaps as acquired through the two

techniques are analysed.

The optimized structure of 3-phenyl-1-tosyl-1H-

pyrazolo[3,4-d]pyrimidin-4-amine, by an ab-initio

(HF) and B3LYP (DFT) methods, in conjugation with


page 206 of 232

6-31G** basis set using Gaussian03, shown in the

following Figure 9.

Figure 7. Correlation circle

Figure 8. Cartesian diagram according to F1-F2.

Figure 9. Optimized geometry of the 3-phenyl-1-tosyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine at HF/6-31G** and B3LYP/6 − 31G** level".


From two methods have been compared and are

described in Table 20, Bond lengths and bond angles

of the optimized structures as obtained. Utilizing HF and DFT methods to detect Total and

HOMO–LUMO energies of the 3-phenyl-1-tosyl-1H-

pyrazolo [3,4-d]pyrimidin-4-amine. The HOMO and

LUMO energies gap are 0.18837 a.u. by HF

and0.17687 a.u. by DFT method, which is very small,

and it indicates that 3-phenyl-1-tosyl-1H-pyrazolo

[3,4-d]pyrimidin-4-amine is chemically highly

reactive and biologically active for charge transfer

intermolecular (Table 21).

On the premise of vibrational analysis at B3LYP/6-

3G** and HF/6-31G** levels, various thermodynamic

parameters are computed and are introduced in Table

22. We calculate the zero point vibrational energies

(ZPVE), rotational constants, thermal energy, heat

capacity and the entropy Svib (T) to the degree of

accuracy it is also clear from Table 22 that the

rotational constant is directly proportional to

rotational temperature. The rotational constant is

inversely proportional to the moment of inertia of the

molecule [70]. Theoretically computed vibrational (IR) frequencies

of 3-phenyl-1-tosyl-1H-pyrazolo[3,4-d]pyrimidin-4-

amine have been contrasted with the experimental

observations [71] which is delineated in Table 23

[72].

Table 20. Comparison of calculated bond lengths (Å) and bond angles (°) using Gaussian03

Bond length (Å) Bond angle (°) Dihedral angle (°)

Parameter HF DFT Parameter HF DFT Parameter HF DFT

C3–C2 1.386 1.408 C2–C3–C4 115.3 114.7 C2–N3–S–O2 −171.9 −172.5

C4–N1 1.326 1.324 C2–N3–N4 111.2 111.9 C3–C2–N3–N4 −1.1 −0.3

C5–N4 1.284 1.476 C3–C5–C6 129.2 130.0 C3–C2–N3–S −180.0 176.9

C6–C5 1.483 1.405 C5–C6–C11 120.6 121.1 C4–C3–C5–C6 5.8 6.5

C6–C11 1.391 1.404 C13–C12–C17 121.2 121.7 C4–C3–C5–N4 −174.1 −173.3

C9–C10 1.385 1.395 N1–C4–C3 119.0 119.6 C4–C3–C2–N2 −1.3 −2.2

C10–C11 1.386 1.784 N1–C4–N5 117.1 116.7 C4–C3–C2–N3 176.5 175.5

C12–S 1.760 1.784 N3–N4–C5 107.4 106.7 C5–N4–N3–C2 1.4 0.7

C13–C12 1.388 1.396 N3–S–C12 103.7 102.7 C5–N4–N3–S −179.6 −176.7


page 207 of 232

C14–C13 1.307 1.393 N3–S–O1 106.1 105.4 C7–C6–C11–C10 0.7 1.2

C15–C14 1.393 1.402 N4–C5–C6 120.3 119.6 C7–C6–C5–C3 −132.6 −141.0

C15–C16 1.390 1.403 N4–N3–S 120.1 119.6 C7–C6–C5–N4 47.2 38.8

N3–S 1.695 1.762 O1–S–O2 121.9 122.9 C11–C6–C5–C3 48.9 40.7

S–O2 1.419 1.455 S–C12–C13 119.2 118.8 C13–C12–S–N3 90.1 97.9

S–O1 .420 1.456 C13–C12–S–O2 −21.9 −13.2

N5–C4 1.341 1.356 C13–C12–S–O1 −157.2 −150.5

C14–C13–C12–S 179.6 178.8

C17–C12–S–O2 157.4 165.5

C17–C12–S–O1 22.1 28.2

C18–C15–C14–C13 −178.5 180.0

C18–C15–C16–C17 178.5 180.0

N2–C2–N3–N4 176.6 177.4

N2–C2–N3–S −2.3 −5.4

N4–N3–S–C12 −105.3 −109.8

N4–N3–S–O2 9.3 4.5

N4–N3–S–O1 139.8 135.6

Table 21. Total and HOMO–LUMO energies of the 3-phenyl-1-tosyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine obtained from HF and DFT methods

HF DFT

Total energy (a.u.) −1509.8034 −1517.3056

Dipole moment (debye) 7.8696 6.7696

HOMO (a.u.) −0.2339 −0.2279

LUMO (a.u.) −0.0455 −0.0511

HOMO–LUMO energy gap(a.u) 0.1884 0.1768

Table 22. Theoretically computed thermodynamical parameters of 3-phenyl-1-tosyl-1H-pyrazolo[3,4-d] pyrimidine-4-amine.

Thermodynamical parameters HF DFT

Zero-point vibrational energy (kcal/mol) 209.6500 194.91907

Rotational temperature (K) 0.01493 0.01490

0.00592 0.00574

0.00531 0.00512

Rotational constants(GHz) 0.31114 0.31050

0.12334 0.11959

0.11060 0.10665

Energy(kcal/mol)

Total 222.472 208.698



page 208 of 232



Molecular capacity at constant volume(cal/mol-K)

Total 78.176 84.769




Entropy (cal/mol-Kelvin)

Total 156.154 161.142




Table 23. Vibrational assignments of fundamental frequencies (cm−1) for 3-phenyl-1-tosyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine at B3LYP/6–311 + G level.

Experimental

frequencies

Theoretical

frequency

Intensity

(km/mol)

Vibrational

Assignments

411 416.10 0.102 Ring out of plane

422.39 6.447 Deformation

430.01 2.932

474 511.51 1.080 C–H out of plane bending

527 530.80 81.554

551 547.35 28.531

637 566.81 263.589

628.03 3.476

693 694.60 21.253 CCC out-of-plane bending

710.96 6.531

776 772.58 22.985 C–H out of plane

807 784.40 33.450 Deformation

824 816.55 16.038

818.62 9.968

828.25 24.525

1003 1010.94 23.630 Inter ring C–C stretching

1019 1016.50 0.445 C–C stretching

1061 1064.67 11.928

1121 1125.82 104.333 In-plane ring HCC bending

1179 1146.28 4.568

1157.45 166.133

1215 1208.88 3.510 C–H in-plane bending

1265 1215.25 6.612

1235.35 1.639

1306 1319.98 32.032 N–N stretching

1339 1334.05 28.455 C–N stretching

1350.16 20.809

1370.97 44.534


page 209 of 232

1396.57 6.135

1443.37 10.438

1466 1443.37 10.438 C–C stretching

1478 1483.85 3.714

1627.16 9.199

1633.95 1.896

1674 1663.74 418.137 NH2 scissoring

3032 3042.48 22.488 Aromatic C–H stretching

3070 3104.35 14.758

3125 3132.14 11.917

3180.85 28.780

3182.30 1.393

3187.92 14.356

3190.31 4.856

3208.22 21.772

3218.57 5.300

3226.66 1.594

3233.78 5.604

3472 3600 85.002 NH2 asymmetric stretching

3736.84 91.085 NH2 symmetric stretching

Scheme 6. Synthesis of 6-methyl-4-APP based carbocyclic nucleoside analogs 26a-e.

2.9. Synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine;

6-methyl-4-APP; 6- methyl-4-amino-pyrazolo[3,4-

d]pyrimidine

Compound 25 a-d obtained by coupling of compound

23 a-d with compound 24 (Mitsunobu coupling).


The structures were limited utilizing Macro model

with Optimized Potentials for Liquid Simulation. Spin

restricted DFT with B3LYP (Becke-3-Lee-Yang-Parr)

density functional and the 6–31-G∗∗ basis set were

used to obtain the calculations.


page 210 of 232

The molecularmechanics (MM) energy optimization

showed that the potential energy of the N2 is higher

than the corresponding N1 isomer as shown in Figure

10.

Figure 10. MM energy analyses showing the N1-regioisomer to have lower energy than N2-isomer.

The quantum mechanics (QM) computation for the

activation energy for the formation of 25a (N1) and

25a (N2) were done. The result demonstrates that the

transition state for N2 higher in energy than that of N1

is 0.0016 Ha (4.27 kJ/mol) (schematic representation

in Figure 11).

The relative energy of is N2 isomer higher than that of

N1 isomer. Thus, QM calculation likewise supports

the formation of N1 product [73].

2.10. Synthesis of fluorine-substituted pyrazolo[3,4-

d]pyrimidine derivative

New fluorine-substituted pyrazolo[3,4-d]pyrimidine

derivatives 29–31 obtained by the reaction of (4-

fluorophenyl)malanonitrile 27 with guanidine, then

forming cyclization reaction with hydrazine producing

2,4-diamino-6-aryl-pyrimidine-5-carbonitrile 28.

Scheme 7 describe fluorinated pyrazolo[3,4-

d]pyrimidine derivatives 30 and 31 that produced

from fluorinated acylation and/or benzeylation of

compound 29 by warming with trifluoroacetamide

and/or 4-fluorobeneyl chloride in acetic acid or dry

C6H6-TEA.

HOMO, LUMO, energy gap, and the optimized

geometric structure of the studied compounds 27-31,

by B3LYP/6-311 + G** theory level, introduced in

Table 24 and Figure 12.

At Figure 12, The LUMO is delocalized among all the

atoms for all molecules, except compounds 30 and 31.

But, the HOMOs are localized on the nitrogen atoms,

except in compounds 27 and 31.

2.10.1. Synthesis of fluorine-substituted

pyrazolo[3,4-d]pyrimidine derivative

The computational calculation of compounds 27-31

was performed by using SPARTAN'08 Windows

graphical software with density functional theory,

DFT/6-31G* basis set [74].

We find theoretically that the compound with lower

LUMO value and higher density value has shown the

highest activity. The theoretical results were found in

good corroboration with the experimental results.

Structure activity relationship studies show that

fluorinesubstituted derivatives play an important role

in antimicrobial activity [75].

3. Synthesis and computational studies of

pyrazolo[1,5-a]pyrimidine

3.1. Synthesis and computational studies of

pyrazolo[1,5-a]pyrimidine

Through a dimroth rearrangement, in quantitative

yields, Derivatives of the new ring system

Pyrazolo[3,4-d] [1,2,3]triazolo[1,5-a]pyrimidine were

synthesized from the comparing angular isomers. This

class of compounds could be the best candidate as

DNA intercalating agents as explained by Preliminary

computational studies.

Figure 11. Schematic representation of the energy barrier for the formation of N1 and N2 isomer.


page 211 of 232

Scheme 7. Synthesis of fluorin-substituted pyrazolo[3,4-d]pyrimidine derivatives.

Figure 12. The electronic densities of HOMO and LUMO for compounds 27–31 using B3LYP/6-311 + G** level of theory.


page 212 of 232

Table 24. Optimized geometric structures and FMO energies of compounds 27 to 31 calculated by using DFT/RB3LYP/6-311 + G** level of theory.

Structures HOMO LUMO Energy gap

eV

-7.452 -3.345 4.107

-6.429 -2.130 4.298

-5.965 -1.857 4.108

-6.813 -2.319 4.494

-7.385 -2.964 4.421

The Dimroth rearrangement (DR), in basic conditions,

could be applied to the angular isomer 33 for

preparing polyheterocyclic ring 34.

The new compounds 38, derivatives of the ring

system Pyrazolo[4,3-d][1,2,3]triazolo[1,5-

a]pyrimidine, were generally isolated in high yields

(70–90%). It appears that in this situation the bond-

forming efficiency relies upon the first reaction step,

comprising in the 1,3-dipolar cycloaddition to form

the triazole moiety [76].

According to the docking scores reported in Table 25

the pyrazolotriazolopyrimidine derivatives 38 and 40

can form stable complexes with DNA.


page 213 of 232

Scheme 8. Synthetic rout to pyrazolo[3,4-d][1,2,3]triazol[1,5-a]pyrimidine core structure.

Scheme 9. Routs to pyrazolo[3,4-d][1,2,3]triazol[1,5-a]pyrimidine ring systems.

Scheme 10. Dimroth rearrangement mechanism.


page 214 of 232

Table 25. DNA fragment docking results (GSCORE)

Entry R1

A B C D E F G H

38a -5.84 -5.76 -7.50 -6.22 -5.69 -7.80 -6.94 -7.54

38b -6.01 -6.10 -7.14 -6.12 -5.91 -7.71 -7.29 -7.02

38c -7.21 7.03 -9.34 -8.33 -7.81 -8.48 -7.61 -6.96

40a -5.62 -5.34 -6.69 -5.72 -5.22 -7.77 -7.47 -6.53

40b -5.56 -5.74 -6.78 -5.75 -5.39 -7.05 -6.95 -6.50

40c -5.82 -5.55 -6.41 -5.17 -5.44 -7.53 -6.81 -6.48

32 (R2=ph) -5.5 -6.19 -7.47 -6.18 -6.06 -8.19 -7.37 -7.16

Mean -5.95 -5.96 -7.33 -6.21 -5.93 -7.79 -7.21 -6.88

A: H; B: (CH2)3COOH; C: (CH2)3NnBu2; D: (CH2)3CONHCH2COOEt; E: (CH2)3COOEt; F: (CH2)3CONH(CH2)2Im; G:

(CH2)3CONHCH(CO2Me)CH2Im; H: (CH2)2(CH2CONH)2-CH(CO2Me)CH2Im.

Scheme 11. Synthesis of pyrazolo [1,5-a]pyrimidines (44 a,b)

The compound 1-(2,4-dimethyl-1,3-thiazol-5-

yl)ethanone (41) was reacted with ethyl formate in

dried ether containing sodium methoxide forming the

sodium salt of 3-hydroxy-1-(2,4-dimethylthiazol-5-yl)

prop-2-en-1-one (42) that react with 3-amino-4-

phenyl-1H-pyrazole or 3-amino-5-phenyl-1H-

pyrazole in glacial acetic acid containing piperidenum

acetate forming 5-(2,4-dimethyl-1,3-thiazol-5-yl)-3(or

4)-phenylpyrazolo[1,5-a]pyrimidines (44a,b).

Frequency computations were performed at a similar

level of the theory in order to characterize the

stationary points and to assess the zero-point energy


page 215 of 232

(ZPE), free energies (G) and enthalpies (H) at 298.15

K. TSS had just a single imaginary frequency.

The 13DC reaction is demonstrated by utilizing the

density functional theory (DFT). We notice a

computational investigation of regioselectivity of 2, 4-

dimethylthiazol 45 dipolarophiles. Our principle

objective in acquiring these cycloadditions to

acrylonitrile results is to compute the energy barrier

for the 13DC reaction. B3LYP technique affirms that

the 47 geometry is favoured by 3.789 kJ.mole-1.

Activation barrier, enthalpy, free energy, and reaction

energies are given in Table 27. As mentioned before,

the studied 13DC reaction prefers structure 47

products with the lower activation energy (72.328 kJ.

mol−1) and high negative estimations of enthalpy and

free energy [77].

Scheme 12. Regioisomeric pathways for the studied cycloaddition reaction

Figure 13. Optimized geometries obtained by B3LYP/6-311 ++G** of all spices in the studied 13DC reaction. The bond lengths are given in angstroms

Table 26. Zero point energy (ZPE), electronic energy (E), enthalpy (H) and free energies (G), total energy (E + ZPE) computed at 298 K of the stationary points involved in the studied 13DC reaction using B3LYP/6-311 ++G** level of theory.

Structure ZPE E H G Et

Au

acrylonitrile 0.05058 −170.88289 −170.82720 −170.85818 −170.83231

45 0.12172 −928.57717 −928.44370 −928.49390 −928.45545

3D 0.11855 −928.49839 −928.36910 −928.41635 −928.37984

TS1 0.17372 −1099.43404 −1099.24270 −1099.30732 −1099.26032

TS2 0.17355 −1099.43868 −1099.24740 −1099.31274 −1099.26513

46 0.17903 −1099.50842 −1099.30020 −1099.37243 −1099.32939

47 0.17858 −1099.50940 −1099.31520 −1099.37487 −1099.33082


page 216 of 232

Table 27. Enthalpies (∆H) and free energies (∆G), barrier energies Efa, Eb

a , relative energies (∆E) computed at 298 K of the stationary points involved in the studied 13DC reaction utilizing B3LYP/6-311 ++G** level of theory

Product

(kJ/mole)

∆H ∆G Efa Eb

a ∆E

46 −273.437 −59.468 −72.328 −182.020 3.789

47 −274.012 −60.043 −65.549 −173.141 0

Scheme 13. Schematic diagram and synthesis route of the investigated dyes.

3.2. Synthesis of triaminopyrazolo[1,5-a]pyrimidine

dyes

We have blended multifunctional dyes 3-(4-methyl-

phenylazo)-6-(4-nitro-phenylazo)-2,5,7-

triaminopyrazolo[1,5-a]pyrimidine 52a and 3-(4-

methyl-phenylazo)-6-(4-acetyl-phenylazo)-2,5,7-tri

aminopyrazolo[1,5-a]pyrimidine 52b, then

characterized by IR, 1H NMR and 13C NMR

techniques. Through density functional theory, the

ground state geometries have been calculated.

This scheme obtain Synthesis of 3-(4-methyl-

phenylazo)-6-(4-nitro-phenylazo)-2,5,7-

Triaminopyrazolo[1,5-a] pyrimidine 52a and 3-(4-

methyl-phenylazo)6-(4-acetyl-phenylazo)-2,5,7-

triaminopyrazolo[1,5-a]pyrimidine 52b.

3.2.1. Synthesis of 3-(4-methyl-phenylazo)-6-(4-

nitro-phenylazo)-2,5,7-

Triaminopyrazolo[1,5-a]pyrimidine 52a and

3-(4-methyl-phenylazo)6-(4-acetyl-

phenylazo)-2,5,7-triaminopyrazolo[1,5-

a]pyrimidine 52b

Schematic diagram and synthesis route of the

investigated dyes depicted in Scheme 8.


page 217 of 232


Energy gap of HOMO–LUMO increases for 52b

while decreases for 52a at ground state. The

introduction of carboxylic group in place of nitro 53,

raise the HOMO and LUMO energies. It was seen that

energy gap of the 52b is greater than the 52b. We

observed decrease in energy gap by using solvent for

52a while solvent has no significant effect for 52b.

Figure 14. The distribution patterns of the frontier molecular orbitals (HOMOs and LUMOs) of 52a and 52b

Table 28. The HOMO energy (EHOMO), LUMO energy (ELUMO) HOMO–LUMO energy gap (Egap) and dipole moment (µ) in eV for ground at B3LYP/6-31G*level of theory.

Dyes EHomo ELumo E gap µ

52a -5.51 -2.62 2.89 14.78

52b -5.29 -2.34 2.94 7.89

52aa -5.60 -2.83 2.77 19.60

52ba -5.47 -2.47 3.00 10.65

53 -5.30 -2.34 2.96 7.70

a The geometries have been optimized in solvent

(methanol).

Table 29. Experimentala and calculated absorption wavelengths (λ) in nm of TD-B3LYP/6-31G* level of theory.

a Experimental absorption wavelengths of 52a 479 nm while 52b

465 nm. b In gas phase. c In solvent (methanol).

Table 30. The ∆Ginject. Oxidation potential, |VRP|, LHE of investigated dyes at TD-B3LYP/6-31G* and PCM-B3LYP/6-31G* level of theory.

System ∆Ginject Eoxdye Eox

dye* λmaxICT LHE ǀVRPǀ

52a -0.86 5.60 3.13 2.46 0.8732 0.43

52b -1.19 5.47 2.80 2.66 0.9799 0.53

53 -1.18 5.50 2.82 2.68 0.9783 0.59

In Table 30, the ∆Ginject, Oxidation potential, and

|VRP| of the studied dyes were presented. The values

of electron injection and electronic coupling constant

for 52a are _0.86 and 0.43, respectively, while 52b are

_1.16 and 0.58, respectively. Al-Sehemi et al.

demonstrated that, (HOMOs) the highest occupied

molecular orbitals and lowest unoccupied molecular

orbitals (LUMO) are delocalized and localized on

throughout the backbone in 52b, respectively. The

HOMO and LUMO energies reduced from gas phase

to solvent.

Solvent plays important role towards elevating the

dipole moment. In solvent, the wavelengths of

maximum absorption are red shifted. Further

improvement towards efficient sensitizers occur when

we attach anchoring groups having strong anchoring

ability along with elongating the bridge as revealed in

this study [78].

3.3. The regiodivergent palladium-catalysed C-H

arylation of Pyrazolo[1,5-a]pyrimidine

F Λ Transition

52ab 1.1183 471 H → L

52bb

0.1549 401 H→ L + 1

0.8718 464 H→ L

52ac

0.4224 383 H→ L + 1

0.8970 504 H→ L

52bc

0.2090 396 H-1→ L + 1

1.6978 466 H→ L

53c 0.4428 370 H-1→ L + 1

1.6651 463 H → L

0.4526 368 H-1→ L + 1


page 218 of 232

As seen in Scheme 9, to achieve site selectivity at C7,

using of the monodentate phosphine ligand SPhos

proved crucial, giving the coveted item 55 a in great

yield.

The HOMO orbital has critical electron density at the

C3 position, and that this position has by far the

highest “electrophile affinity” (Eα) value (Figure 15a)

[79], on the other hand, they focused the significantly

greater acidity of the C7-H group as detected by

comparing the computed relative energies for the

removal of each of the protons by acetate (Figure 15b)

[80].

Scheme 14. Results of optimization of reaction conditions.

3.4. Synthesis of Pyrazolo[1,5-a]pyrimidin-7(4H)-one

Electronic absorption bands were observed and

compared with the predicted transitions using a time-

dependent DFT method (TDDFT). In all solvents

utilized, except for DMF and acetonitrile, compounds

58 and 59 presented azo-hydrazone tautomerism.

However, the ionized species were predominant in

highly polar solvents for compounds 60 and 61. In

DMF, based on the molecular structure, all the

investigated dyes presented either in acid-base

equilibrium or in the ionized form. Hence, the values

of the ionization constant (Kion) and Gibbs free

energy (ΔG) of the equilibrium existing in solution

were computed. In addition, the pKa values of the

dyes is calculated by using the spectrophotometric

method [81].

3.4.1. Quantum chemical calculations

The full geometrical optimization of the isolated

molecules 58-61 is in this scheme. The transfer of the

hydrogen atom related to N4 either to the keto-oxygen

(O8) or to N11 creates annular and azo-hydrazone

tautomerism, respectively. In addition, it is well-

known that a variety of azo dyes can co-exist in acid-


page 219 of 232

base equilibrium particularly in basic solvents [82-

84].

Using the B3LYP functional, The DFT calculations

were calculated, in which Becke’s nonlocal exchange

[85,86] and the Lee-Yang-Parr correlation functional

were used [46]. Compiles selected structural

parameters detected only by geometrical optimization

since no experimental geometrical data are shown in

the literature for NH, OH and hydrazone tautomers

calculated at PM6 levels and DFT.

Dissection of the spatial structure of the dyes 58-61

has uncovered that the fused heterocyclic fragment is

completely planar in both NH and OH shapes but

deviates slightly from planarity in the hydrazone

tautomers as the torsion C6C7N1aN1 angle.

We can observe in Table 32, the NH tautomers have

the lowest energy value among all the potential

tautomers calculated at the B3LYP/6-31G**

computational level.

Figure 15. Results of DFT computational are summarized. a) Left: calculated (B3LYP-d2/6-311+ +G (d)) HOMO for 54 (isovalue ±0.05 (electron/ bohr3)1/2), right: gas-phase electrophile affinity (Eα) values, determined using Br+ as test electrophile (B3LYP/6-311+G (2d, 2p)). b) Calculated (B3LYP/6-311+ +G (2df, 2p)//B3LYP/6-31G (d)) free energies for the deprotonation of each of the CH groups of 54 by acetate

Scheme 15. Compounds and equilibria (298K0, equibrium constant) investigated with the number of atoms indicated

Table 31. The calculated (DFT, PM6) structural parameters (bond length in Å, angles in degree) of compounds 58-61.

Compound Parameter DFT PM6

NH OH Hyd NH OH Hyd

58 N4C5 1.380 1.330 1.379 1.403 1.352 1.406

C6C7 1.462 1.385 1.452 1.457 1.393 1.451

C7O8 1.215 1.340 1.219 1.201 1.356 1.204

N10N11 1.281 1.281 1.314 1.265 1.265 1.309

N10N11C4-C5

- -174.887 - 177.839 -179.185 -173.697 -178.991 -179.366

C6C7N1aN1 -179.661 -179.861 178.404 -179.879 -179.942 -178.588

C2C3N10N11 1.074 -0.297 -0.732 4.359 1.692 -2.112


page 220 of 232

N2-N1

-C6-C7

- -162.192 161.417 21.021 -166.871 -167.524 -165.775

59 N3C4 1.381 1.336 1.380 1.401 1.349 1.406

C5C6 1.460 1.385 1.450 1.458 1.392 1.454

C7O8 1.216 1.340 1.219 1.201 1.356 1.204

N9N10 1.281 1.281 1.313 1.265 1.265 1.308

N10N11C4-C5

- 179.261ـ 177.697ـ 174.948ـ 179.148ـ 178.947ـ 176.320ـ

C6C7N1aN1 179.694 -179.998 -178.00 -179.960 -179.931 -178.756

C2C3N10N11 1.764 -0.229 0.996 4.343 1.883 -1.814

C6C5C12C13 - 142.923 -161.981 -159.292 -112.810 -135.209 -136.199

N2-N1

-C6-C7

- -160.657 161.023 -159.227 -166.834 -167.353 -165.640

60 N3C4 1.381 1.331 1.381 1.405 1.353 1.413

C5C6 1.462 1.385 1.453 1.455 1.393 1.454

C7O8 1.214 1.338 1.218 1.200 1.354 1.203

N9N10 1.279 1.279 1.318 1.263 1.265 1.325

N10N11C3-C2

- 178.850 -179.779 -175.332 -29.635 -179.378 -7.945

C6C7N1aN1 179.848 -179.995 -178.321 179.814 179.930 -178.645

C2C3N10N11 -0.521 0.038 0.555 0.148 -1.313 1.761

61 N3C4 1.382 1.337 1.383 1.403 1.354 1.412

C5C6 1.459 1.385 1.451 1.457 1.393 1.456

C7O8 1.215 1.339 1.219 1.200 1.354 1.203

N9N10 1.279 1.280 1.318 1.263 1.265 1.324

N10N11C3-C2

- 178.773 179.633 -175.890 28.007 175.766 8.254

C6C7N1aN1 -179.869 179.963 177.744 -179.627 -179.869 178.746

C2C3N10N11 -0.870 -0.106 -0.739 -0.288 1.196 -1.763

C6C5C12C13 143.186 163.404 161.144 -116.397 140.751 -143.109

Table 32. Physicochemical features of the different tautomeric forms of compounds 58-61. A piece of evidence supporting the above finding is the negative values of the computed HOMO and LUMO energies-following a full geometry optimization- by DFT for all the expected tautomers.

Computational

level

Δ E Natural.charge at N11 HOMO LUMO Ega Eg

b ln298KIoc

NH OH Hyd NH OH Hyd NH OH Hyd NH OH Hyd

58

DFT 0.00 31.39 16.27 -

0.260

-

0.274

-

0.341

-

0.196

-

0.183

-

0.202

-

0.072

-

0.060

-

0.095

2.86 2.47 2.41

(2.07)

DFT

(PCMeDMSO)

0.00 27.40 17.56 -

0.283

-

0.274

-

0.316

-

0.202

-

0.183

-

0.206

-

0.075

-

0.060

-

0.096

2.93 2.54 2.37

(1.96)

DFT (PCM e

C2H5OH)

0.00 28.09 17.81 -

0.274

-

0.280

-

0.316

-

0.202

-

0.186

-

0.206

-

0.075

-

0.063

-

0.096

2.93 2.54 2.40

(1.97)

DFT (PCM e

Acetone)

0.00 28.03 17.24 -

0.271

-

0.286

-

0.321

-

0.202

-

0.189

-

0.207

-

0.075

-

0.065

-

0.096

2.93 2.56 2.40

(1.94)

DFT (PCM e

CHCl3)

0.00 30.99 16.85 -

0.268

-

0.281

-

0.328

-

0.200

-

0.186

-

0.206

-

0.074

-

0.063

-

0.096

2.91 2.54 2.50

(1.92)

DFT (PCM e

CCl4)

0.00 31.63 17.78 -

0.268

-

0.281

-

0.328

-

0.200

-

0.186

-

0.206

-

0.074

-

0.063

-

0.096

2.91 2.54 2.52

(1.97)

59


page 221 of 232

DFT 0.00 26.26 15.75 -

0.261

-

0.274

-

0.339

-

0.196

-

0.190

-

0.202

-

0.072

-

0.064

-

0.097

2.86 2.42 2.37

(2.02)

DFT

(PCMeDMSO)

0.00 21.31 13.99 -

0.268

-

0.293

-

0.335

-

0.202

-

0.193

-

0.208

-

0.076

-

0.072

-

0.099

2.91 2.51 2.08

(1.71)

DFT (PCM e

C2H5OH)

0.00 22.12 14.04 -

0.268

-

0.293

-

0.335

-

0.202

-

0.193

-

0.208

-

0.076

-

0.072

-

0.099

2.91 2.51 2.14

(1.72)

DFT (PCM e

Acetone)

0.00 22.42 13.78 -

0.271

-

0.294

-

0.318

-

0.202

-

0.193

-

0.208

-

0.076

-

0.073

-

0.098

2.91 2.54 2.15

(1.70)

DFT (PCM e

CHCl3)

0.00 24.73 13.64 -

0.265

-

0.289

-

0.331

-

0.198

-

0.192

-

0.205

-

0.074

-

0.072

-

0.098

2.86 2.47 2.25

(1.69)

DFT (PCM e

CCl4)

0.00 26.41 14.10 -

0.265

-

0.289

-

0.331

-

0.198

-

0.192

-

0.205

-

0.074

-

0.072

-

0.098

2.86 2.47 2.32

(1.72)

60

DFT 0.00 35.40 31.51

-

0.276

-

0.293

-

0.350

-

0.216

-

0.204

-

0.215

-

0.082

-

0.069

-

0.106

2.86 2.44

(2.61)

DFT

(PCMeDMSO)

0.00 28.88 23.63 -

0.284

-

0.309

-

0.344

-

0.215

-

0.205

-

0.218

-

0.081

-

0.076

-

0.102

2.91 2.45

(2.28)

DFT (PCM e

C2H5OH)

0.00 28.88 26.26 -

0.286

-

0.303

-

0.343

-

0.215

-

0.205

-

0.216

-

0.081

-

0.076

-

0.104

2.91 2.47

(2.30)

DFT (PCM e

Acetone)

0.00 31.51 26.26 -

0.286

-

0.305

-

0.333

-

0.215

-

0.205

-

0.217

-

0.081

-

0.076

-

0.102

2.91 2.64

(2.48)

DFT (PCM e

CHCl3)

0.00 31.51 26.26 -

0.281

-

0.302

-

0.345

-

0.216

-

0.204

-

0.215

-

0.082

-

0.074

-

0.106

2.86 2.55

(2.34)

DFT (PCM e

CCl4)

0.00 34.13 28.88 -

0.278

-

0.309

-

0.343

-

0.216

-

0.205

-

0.216

-

0.082

-

0.076

-

0.104

2.86 2.61

(2.41)

61

DFT 0.00 30.96 29.32 -

0.276

-

0.294

-

0.349

-

0.215

-

0.205

-

0.215

-

0.082

-

0.072

-

0.108

3.07 2.40

(2.50)

DFT

(PCMeDMSO)

0.00 23.63 21.00 -

0.282

-

0.310

-

0.349

-

0.215

-

0.206

-

0.215

-

0.082

-

0.079

-

0.108

3.07 2.23

(2.12)

DFT (PCM e

C2H5OH)

0.00 26.26 23.63 -

0.283

-

0.307

-

0.328

-

0.215

-

0.206

-

0.218

-

0.082

-

0.079

-

0.104

3.07 2.28

(2.18)

DFT (PCM e

Acetone)

0.00 23.63 21.00 -

0.281

-

0.299

-

0.328

-

0.215

-

0.202

-

0.218

-

0.082

-

0.075

-

0.104

3.07 2.27

(2.15)

DFT (PCM e

CHCl3)

0.00 28.88 23.63 -

0.280

-

0.294

-

0.342

-

0.215

-

0.201

-

0.216

-

0.083

-

0.075

-

0.106

3.04 2.37

(2.22)

DFT (PCM e

CCl4)

0.00 28.88 26.26 -

0.278

-

0.299

-

0.342

-

0.215

-

0.202

-

0.216

-

0.083

-

0.075

-

0.106

3.04 2.45

(2.31)


page 222 of 232

ΔE in kJ/mol, is the energy difference between OH,

hydrazone and the NH forms. Ega, Eg

b in kcal/mol, are

the energy gap between LUMO and HOMO for NH

and hydrazone forms, respectively. The equilibrium

constant values were obtained from ln298 Ko = -

ΔGo/RT equation. c Values in parentheses represent the ln298KII

o of the

NHNHhydrazone equilibrium. HOMO and LUMO,

in eV, indicate the energies of the highest occupied

and lowest unoccupied molecular orbitals.

The sensitivity of its λmax to the type of the substituent

attached and the nature of the solvent. This CT

originates mainly from the pyrazolo[1,5-a]pyrimidine-

7-(4H)-one ring as a donor to the terminal

heterocyclic moiety.

Electronic absorption spectra from time-dependent

DFT calculations of the tautomers were expected here

in Table 34.

The values of ΔG and Kion of the ionization

equilibrium existing in solution are cited in Table 35.

The negative values of the free energy change of the

ionization process indicate that this process is

spontaneous. In general, the experimental results

presented in this table show that the values of Kion and

ΔG of the compounds investigated in mixed solvent

depend upon R and increase in the following sequence

58 (R=CH3)> 59 (R=Ph) and 60 (R=CH3) >61 (R=Ph)

Values of pKa were determined by using three

different spectrophotometric methods, namely the half

curve-height, the limiting absorbance and the

isosbestic point methods [87, 88]. The obtained values

are in Table 36.

The similarity between the experimental and

theoretical results shows that the DFT/B3LYP/6-

31G** method has powerful role in explaining the

features and tautomeric phenomena of the compounds

under investigation. In the light of the obtained

calculations of the energy gap (ԐLUMO_ԐHOMO) and

time-dependent DFT, the visible absorption bands of

compounds 58 and 59 are successfully assigned. The

phenyl substituent at C5 in compound 59 diminishes

the energy gap between HOMO and LUMO and

consequently absorbs light at relatively long

wavelengths relative to compound [81].

Table 33. Experimental electronic absorption compounds havig spectral data of 58-61 moiety.

Compound C2H5OH DMF DMSO CH3CN Acetone CHCl3 CCl4

λmax Log Ԑ λmax log Ԑ λmax log Ԑ λmax log Ԑ λmax log

Ԑ

λmax log

Ԑ

λmax log Ԑ

58 404 4.48 440 4.38 426 4.29 442 4.34 407 4.33 405 4.38 405sh 4.30

367 4.56 375sh 4.13 375sh 4.19 367sh 3.88 370 4.38 370 4.46 373 4.38

246 4.52

208 4.61

59 438sh 4.41 454 4.60 452sh 4.33 438 4.52 448sh 4.02 409 4.49 410 4.47

415 4.48 372 4.10 423 4.37 372sh 4.08 412 4.46 372 4.55 372 4.55

374sh 4.36 376sh 4.24 372 4.44

257 4.66

217 5.10

60 430 4.26 451 4.25 439 3.99 436 4.19 428sh 3.90 374 4.06 376 4.21

280 3.80 385 4.02 377 4.02

236sh 4.24

209 4.58

61 436 4.48 457 4.54 458 4.41 431 4.45 447 4.46 410 4.27 405 4.24

297 4.05

253 4.57

215 4.94

λmax ــ position of band maxima in absorption spectra (in nm), Ԑــ absorption coefficients (in M-1 cm-1), sh - shoulder.


page 223 of 232

Table 34. Wavelengths (λnm) and oscillator strengths (ƒ) of electronic absorption transitions calculated at TDDFT method and the transition energies of the experimental (CT) absorption bands.

Compound Time-dependent DFT calculations ET (kJ/mol)

NH OH hyd

λ (nm) Ƒ λ (nm) ƒ λ (nm) ƒ NH Hyd

58 386 0.62 399 0.78 464 0.52 0.33 0.30

340 0.18 331 0.12 347 0.08

248 0.19 251 0.22 259 0.06

214 0.05 217 0.01

59 394 0.52 429 0.32 415 0.10 0.32 0.29

343 0.09 378 0.25 361 0.13

249 0.19 293 0.16 260 0.26

226 0.21 244 0.10 213 0.03

60 356 0.82 369 0.64 455 0.39 0.28

286 0.12 315 0.12 364 0.11

212 0.08 262 0.13 342 0.24

209 0.11 232 0.40 246 0.09

61 362 0.74 396 0.45 468 0.28 0.27

256 0.04 344 0.55 422 0.18

218 0.02 273 0.23 360 0.22

218 0.18 256 0.24

245 0.10

Table 35. Values of Kion and -ΔG for the ionization process of the investigated compounds

System Compound

58 59 60 61

Kion -Δ G Kion -Δ G Kion -Δ G Kion -Δ G

DMFــC2H5OH 11.01 1.42 4.20 0.85 7.52 1.19 5.07 0.96

DMFــacetone 6.84 1.14 5.31 0.96 5.84 1.04 3.41 0.73

DMFــCHCl3 10.78 1.40 6.07 1.10 7.03 1.15 4.65 0.91

DMFــCCl4 9.79 1.35 3.45 0.73 6.63 1.12 4.21 0.85

Table 36. Values of acidity constants (pKa) and lamda max of the neutral and ionic forms of the compounds 58-61

Compound pKa SD λ max, nm

Method 1 Method 2 Method 3 Mean Neutral Ionic

58 8.67 8.60 8.66 8.64 ±0.04 366 425

59 7.38 7.39 7.25 7.34 ±0.08 366 430

60 7.23 7.23 7.20 7.22 ±0.02 372 425

61 6.32 6.19 6.33 6.28 ±0.08 370 429

3.5. Synthesis of 7-hydroxy-6-phenyl-3-

(phenyldiazenyl)Pyrazolo[1,5-a]pyrimidine-

2,5(1H,4H)-Dione

Synthesise of 7-hydroxy-6-phenyl-3-

(phenyldiazenyl)pyrazolo[1,5-a]pyrimidine-

2,5(1H,4H)-dione derivatives were obtained from the

reaction of (chlorocarbonyl)phenyl ketene and 5-

aminopyrazolones produce great yields and take short

reaction times. To optimize the structures, calculate

the energies and vibrational frequencies IR and 1H

NMR shielding tensors of the desired products by


page 224 of 232

using Density Functional Theory (DFT). There are

new methods to synthesize heterocyclic compounds

by using condensation of (chlorocarbonyl) ketenes 63

with 1,3-dinucleophiles [89-91]. The reaction of

(chlorocarbonyl) ketenes 63 with 5-aminopyrazoles

62 for the synthesis of 7-hydroxy-6-phenyl-3-

(phenyldiazenyl)Pyrazolo[1,5-a]pyrimidine-2, 5(1H,

4H)-Dione derivatives 64a-e, is reported in Scheme

16.

The endocyclic nitrogen atom will attack the central

carbon atom of the ketene group, which have a low-

lying LUMO. Subsequent cyclization gives compound

66. Compound 64a-e is given by H+ elimination.

3.5.1. Theoretical studies

To anticipate the spectroscopic properties of the most

stable structure, DFT approach was utilized in the

Gaussian software. The computed wave numbers were

scaled with the scaling factor in order to figure out

how the predicted vibrational spectra are in agreement

with experimental ones.

Vibrational examination of molecule was computed

by using B3LYP level with basis set 6-311 G. The

identified and predicted vibrational spectrum with

results of fundamental vibrational modes were given

in Table 37.

Table 37, in the range of 3300-2800 cm−1 the

experimental N-H and O-H stretching frequencies

showed for compound 64a-e, the theoretically

presaged IR for N-H and O-H stretching frequencies

too were seen in the same range ~ 3199-2902 cm-1

by B3LYP/6-311G. The strongly intense peaks from

B3LYP/6-311+G (d,p) agree well to the intensities

obtained experimentally.

Scheme 16. Synthesis of 7-hydroxy-6-phenyl-3-(phenyldiazenyl)Pyrazolo[1,5-a]pyrimidine-2, 5(1H,4H)-dione derivatives 64a-e.

Scheme 17. Proposed mechanism for the formation of 7-hydroxy-6-phenyl-3-(aryldiazenyl)Pyrazolo[1,5-a]pyrimidine-2, 5(1H,4H)-dione derivatives.

Table 37. Calculated IR frequency of synthesized compound by B3LYP/6-311G

Compound Experimental IR(cm-1) Theoretical IR(cm-1) B3LYP/6-311G

64a (NH,OH) 3200-2900,(C=O) 1657 ,1625,1481,1550 (NH,OH) 3209-2902,(C=O) 1651,1660,1624,1633,

1543,1552,1480,1489

64b (NH,OH) 3200-2900,(C=O) 1668,1628,1554,1491 (NH,OH) 3199-2893,(C=O) 1669,1624,1633,

1552,1489,1498

64c (NH,OH)3200-2900,(C=O) 1672,1593,1549,1484 (NH,OH) 3209-2902,(C=O) 1670,1679,1588,1597,

1543,1480,1489

64d (NH,OH)3200-2900,(C=O) 1672,1628,1552,1492 (NH,OH) 3207-2902,(C=O) 1669,1678,1624,1633,1552,

1561,1489,1498

64e (NH2) 3639,3547,(NH,OH)3300-2800,(C=O)

1688,1630,1596,1486

(NH,OH) 3325-2803,(C=O) 1687,1624,1633,1642,1588,

1597,1480,1489


page 225 of 232

Figure 16. The optimized geometries of the compounds 64a-e

Table 38. The Nuclear Magnetic Resonance spectra of the ground state geometry of molecule has been indicated by DFT/GIAO method". To calculate isotropic nuclear magnetic used The GIAO method that is one of the most common methods. In table the predicted and measured NMR values were listed by B3LYP/6-311G

Experimental NMR(ppm) Theoretical NMR(ppm) B3LYP/6-311G

13C NMR 13C NMR

64a 64b 64c 64d 64e 64a 64b 64c 64d 64e

160.04 160.58 161.13 160.08 160.52 159.71 159.06 159.51 159.83 159.00

159.80 160.48 160.35 159.85 160.43 154.94 157.75 152.63 153.00 156.16

151.36 158.78 151.36 151.31 153.78 149.63 149.75 149.28 149.69 155.05

145.94 150.49 145.54 146.12 145.48 145.92 149.24 146.56 145.66 148.70

143.69 146.20 134.50 141.10 141.66 130.44 140.89 146.12 136.29 147.12

134.35 134.59 131.10 136.81 134.48 129.65 132.99 130.44 130.45 130.50

129.22 129.26 130.39 134.47 130.52 128.24 129.31 130.05 129.96 127.93

127.51 126.48 129.54 129.80 129.82 127.96 128.17 129.69 128.73 126.36

126.88 123.32 127.48 127.61 128.29 126.29 127.62 127.68 128.15 125.68

123.31 119.88 123.26 123.40 127.60 125.97 123.34 126.08 126.90 122.12

123.01 118.51 120.23 123.10 123.42 124.19 118.31 125.51 125.90 120.93

117.76 114.70 116.85 117.77 118.41 115.81 116.19 115.83 115.76 115.94

84.32 84.26 84.27 84.40 84.48 110.77 104.55 110.85 110.29 108.90

67.93 66.30 67.64 64.85 67.02 100.40 96.46 101.71 100.34 103.17

55.46 20.62 50.13 15.37

Table 39. Showing Gibbs free energy for each compound at 298 K. According to these data, the reactant has Energy surface lower than the product energy surface at room temperature. This happen obtained the reaction will be done by external energy.

Comp 63 62a 62b 62c 62d 62e 64a 64b 64c 64d 64e THF HCl

∆G°f

(j)×104 -2.51 -1.83 -6.70 -4.86 -6.53 -1.04 -3.13 -3.43 -4.34 -6.67 -4.72 -6.10 -1.21


page 226 of 232

Where 7-hydroxy-6-phenyl-3-(phenyldi azenyl)

Pyrazolo[1,5-a]pyrimidine-2,5(1H,4H)-dione 62a 7-

hydroxy-3-((4-methoxyphenyl)diazenyl)-6-pheny

lpyrazolo[1,5-a]pyrimidine-2,5(1H,4H)-dio ne 62b ,

3-(4-chlorophenyl) diazenyl)-7-hydroxy-6-phenyl

pyrazolo[1,5-a]pyrimidine-2,5(1H,4H)-dione 62c ,7-

hydroxy-6-phenyl-3-(p-tolyldiaze nyl)Pyrazolo [1,5-

a]pyrimidine-2,5(1H,4H)-dione 62d, 4-((7-hydroxy-

2,5-dioxo-6-phenyl-1,2,4,5-tetrahydropy razolo[1,5-

a]pyrimidin-3-yl)diazenyl) benzenesulfonamide 62e.

Activity energy surface of reactant and product in

THF depicted in Figure 17.

Calculation by Gibbs free energy accordance with

experimental process illustrated this reaction can be

done at THF boiling point, correct products of this

reaction also showed by using NMR data also

showed in the experiment . Calculated parameters

predicted that this reaction theoretically suitable for

experimental synthesis [92].

Figure 17. Activity energy surface of reactant and product in THF.

3.6. Synthesis of 5-tolyl-2-phenylpyrazolo[1,5-

c]pyrimidine-7(6H)thione(Tolyl), 5-tolyl-2-phe-

enylpyrazolo[1,5-c] pyrimidine-7(6H)one(Inon)

It was investigated as corrosion inhibitors utilizing

density functional theory (DFT) at the B3LYP/6-31 +

G (d, p) level of theory. The computed quantum

chemical parameters associated to the inhibition

proficiency are: the highest occupied molecular orbital

energy (EHOMO), the lowest unoccupied molecular

orbital energy (ELUMO), the energy gap (ΔEL-H),

ionization energy (I), dipole moment (μ), electron

affinity (A), absolute electronegativity (χ), absolute

softness (σ), absolute hardness (η), the fraction of

electron transferred (∆N), and the total energy (Etot)

which were studied.

Figure 18 shows the optimized structures of Tolyl

and Inon inhibitors along with atomic numbering. For

Tolyl and Inon molecules, the computed quantum

chemical properties as EHOMO, ELUMO, ΔEL−H and

dipole moment (μ) are obtained in Table 40.

Table 40. Calculated quantum chemical parameters of Tolyl and Inon molecules calculated at B3LYP/6-31 + G (d, p) level of theory

Quantum parameters Unit Tolyl Inon

EHOMO (eV) −0.21463 −0.21943

ELUMO (eV) −0.06821 −0.06535

∆EL –H (eV) 0.14642 0.15408

µ (debye) 7.2231 6.8992

Table 41. Calculated quantum chemical parameters of Tolyl and Inon molecules calculated at B3LYP/6-31 + G(d,p) level of theory.

Quantum parameters Unit Tolyl Inon

I=-EHOMO (au) 0.21463 0.21943

A=-ELUMO (au) 0.06821 0.06535

χ =(I+A)/2

(au) 0.14142 0.14239

η =(i-A)/2 (au) 0.07321 0.07704

σ =1/ η (au−1) 13.65934 12.98027

ω=μ2/2 η (au) 356.32546 308.92370

∆N=( χ FE- χ inh)/2(η fe+

η inh)

46.84182

44.50681

Etot (au) −1295.56608 −972.61603

Tolyl with the softness value of 13.65934 eV has the

most elevated inhibition efficiency contrasted with

12.98027 eV of Inon; this result is also in agreement

with the experimental finding.

Utilizing the DFT/B3LYP/6-31 + G (d,p) level of

hypothesis, the inhibition efficiency of two

Pyrazolo[1,5-c] pyrimidine derivatives is indicated

prompting the accompanying conclusions.

Through DFT calculations, a relationship between

parameters identified with the electronic and

molecular structures of these derivatives and their

ability to stop the corrosion process could be set up.

The inhibition efficiency of these derivatives acquired

quantum chemically increases with the increase in

EHOMO, and decrease in ELUMO and energy gap ΔEL−H.

Tolyl has the highest inhibition efficiency because it

had the highest HOMO energy [93].


page 227 of 232

Figure 18. Optimized geometries of 67 Tolyl and 68 Inon molecules along with atomic numbering calculated at B3LYP/6-31 + G(d, p) level of theory

Figure 19. Frontier molecular orbitals (FMO) of Tolyl and Inon molecules calculated at B3LYP/6-31 + G(d,p) level of theory

4. Conclusion

In this study, the synthesis of different

pyrazolopyrmidines derivatives and their

computational analysis by density functional theory

level (utilizing HF/6−311+G and B3LYP/6−311+G)

were evaluated. Charge transfer occured through the

molecule was shown by calculating the HOMO and

LUMO energies. The electric dipole moment values

(l) of the molecule were counted as calculations of the

DFT. Some geometrical and structural parameters

including, the total energies (E), relative energies

(DE), (bond length in Å, angles in degree), energy

gap, relative Gibbs free energy, dipole moment, and

molecular electrostatic potentials (MEP) were studied.

Acknowledgement

The authors would like appreciate Dr. Yasser Zaky,

from Organic Chemistry, Faculty of Science, Beni-

Suef University, Mrs. Ghada Mayhoob and Arwa Ali

from the Faculty of Science, Beni-Suef University for

their support.

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How to cite this manuscript: Hussein S. H. Mohamed, Sayed A. Ahmed, Reviewing of Synthesis

and Computational Studies of Pyrazolo Pyrimidine Derivatives, Journal of Chemical Reviews,

2019, 1(3), 183-232.

reviewing of synthesis and computational studies of ... · derivatives are shown to exhibit...

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